JP7223764B2 - CXCR2 antagonist - Google Patents

Description

The present invention claims priority to:
CN201810027003.2, filing date: 2018.01.11.

The present invention relates to compounds as CXCR2 antagonists and their use in the preparation of medicaments as CXCR2 antagonists. Specifically, it relates to a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.

Chronic obstructive pulmonary disease (COPD) is a debilitating disease characterized by progressive airflow limitation caused by chronic airway inflammation. It is usually caused by inhaling harmful particles and gases, mainly from smoking and air pollution. Its symptoms include excessive mucus secretion, airway narrowing, fibrosis, and alveolar loss. It can lead to average weight loss, osteoporosis, cardiovascular disease and psychological damage. Current treatments for moderate-to-severe chronic obstructive pulmonary disease are relatively ineffective, and no drug can significantly reduce disease progression or death. The Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) recommends the use of long-acting bronchiectasis (LABA and LAMA) as first-line maintenance therapy for patients with moderate to severe COPD. Although these drugs produce effective bronchiectasis, they fail to treat the underlying inflammation in patients with chronic obstructive pulmonary disease. Inhaled glucocorticoids (ICS) have some benefit in asthma patients but little benefit in chronic obstructive pulmonary disease. Therefore, if bronchodilators are ineffective in a patient, additional therapeutic modalities, including inhaled glucocorticoids (ICS), should only be used with caution.

COPD is a chronic inflammatory disease, and effective anti-inflammatory therapy represents one of the greatest unmet therapeutic needs currently in the field of chronic obstructive pulmonary disease. Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor and the first oral anti-inflammatory drug approved for the treatment of chronic obstructive pulmonary disease. However, since roflumilast is limited due to its strong side effects, there is a need to develop other new anti-inflammatory targets for the treatment of chronic obstructive pulmonary disease.

Interleukin-8 (IL-8 or CXCL8) is a protein containing 72 amino acid residues and is a key factor controlling leukocyte recruitment and migration at sites of inflammation. Interleukin-8 functions by binding to its receptor, a G protein-coupled receptor belonging to the CXC chemokine receptor family, including CXCR1 and CXCR2. CXCR2 is highly expressed on the surface of human neutrophils and when interleukin-8 binds to CXCR2 on the surface of neutrophils, it induces a series of intracellular events such as changes in calcium flux, degranulation and subsequent chemotaxis. provoke a reaction. Interleukin-8 is elevated in various inflammatory diseases such as arthritis, asthma and chronic obstructive pulmonary disease, indicating that blocking its interaction with its receptor is beneficial in these diseases. ing.

Ｄａｎｉｒｉｘｉｎ WO2007124424 disclosed the use of the CXCR2 antagonist Danirixin in the treatment of related diseases.

Danirixin

ここで、
Ｔ_１は、Ｃ（Ｒ_２Ｒ_３）およびＮ（Ｒ_４）から選択され、
環Ａは、５～６員ヘテロアリールおよびフェニルから選択され、前記５～６員ヘテロアリールおよびフェニルは、選択的に１、２または３個のＲ_ａによって置換され、
Ｒ_１は、Ｃ_１－６アルキル、ＮＨ_２－（Ｃ＝Ｏ）－Ｃ_１－３アルキル－、５～１０員ヘテロアリール－Ｃ_１－３アルキル－、Ｃ_３－７シクロアルキル、５～９員ヘテロシクロアルキル、５～１０員ヘテロアリール、フェニル、－Ｃ_１－６アルキル－フェニルから選択され、前記Ｃ_１－６アルキル、ＮＨ_２－（Ｃ＝Ｏ）－Ｃ_１－３アルキル－、５～１０員ヘテロアリール－Ｃ_１－３アルキル－、Ｃ_３－７シクロアルキル、５～９員ヘテロシクロアルキル、５～１０員ヘテロアリール、フェニル、－Ｃ_１－６アルキル－フェニルは、選択的に１、２または３個のＲによって置換され、
Ｒ_２およびＲ_３は、それぞれ独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、ＮＨ_２および選択的に１、２または３個のＲ_ｂによって置換されたＣ_１－３アルキルから選択され、
Ｒ_４は、Ｈおよび選択的に１、２または３個のＲ_ｃによって置換されたＣ_１－３アルキルから選択され、
Ｒ_ａは、それぞれ独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、ＮＨ_２および選択的に１、２または３個のＲ’によって置換されたＣ_１－３アルキルから選択され、
Ｒ_ｂおよびＲ_ｃは、それぞれ独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨおよびＮＨ_２から選択され、
Ｒは、それぞれ独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、ＮＨ_２、Ｃ_１－３アルキル、Ｃ_１－３アルキル－（Ｃ＝Ｏ）－ＮＨ－、Ｃ_１－３アルキル－Ｏ－（Ｃ＝Ｏ）－ＮＨ－、Ｃ_３－６シクロアルキル－（Ｃ＝Ｏ）－ＮＨ－およびＣ_１－６アルキル－Ｏ－（Ｃ＝Ｏ）－から選択され、前記Ｃ_１－３アルキル、Ｃ_１－３アルキル－（Ｃ＝Ｏ）－ＮＨ－、Ｃ_３－６シクロアルキル－（Ｃ＝Ｏ）－ＮＨ－またはＣ_１－６アルキル－Ｏ－（Ｃ＝Ｏ）－は、選択的に１、２または３個のＲ’によって置換され、
Ｒ’は、それぞれ独立して、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨおよびＮＨ_２から選択され、
前記５～６員ヘテロアリール、５～１０員ヘテロアリールおよび５～９員ヘテロシクロアルキルは、それぞれ１、２、３または４個の独立して－ＮＨ－、－Ｃ（＝Ｏ）－、－Ｏ－、－Ｓ－およびＮから選択されるヘテロ原子またはヘテロ原子団を含む、化合物、その異性体またはその薬学的に許容される塩を提供する。 The present invention provides a compound of formula (II), an isomer thereof or a pharmaceutically acceptable salt thereof,

here,
T ₁ is selected from C(R ₂ R ₃ ) and N(R ₄ );
ring A is selected from 5- to 6-membered heteroaryl and phenyl, said 5- to 6-membered heteroaryl and phenyl optionally substituted by 1, 2 or 3 R _a ;
R ₁ is C _1-6 alkyl, NH ₂ —(C═O)—C _1-3 alkyl-, 5-10 membered heteroaryl-C _1-3 alkyl-, C _3-7 cycloalkyl, 5-9 selected from membered heterocycloalkyl, 5- to 10-membered heteroaryl, phenyl, —C _1-6 alkyl-phenyl, said C _1-6 alkyl, NH ₂ —(C═O)—C _1-3 alkyl-, 5 ~10 membered heteroaryl-C _1-3 alkyl-, C _3-7 cycloalkyl, 5-9 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, -C _1-6 alkyl-phenyl is optionally substituted by 1, 2 or 3 R,
R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl optionally substituted by 1, 2 or 3 R _b is,
R ₄ is selected from H and C _1-3 alkyl optionally substituted by 1, 2 or 3 R _c ;
each R _a is independently selected from H, F, Cl, Br, I, OH, _NH2 and C _1-3 alkyl optionally substituted by 1, 2 or 3 R′;
_Rb and _Rc are each independently selected from H, F, Cl, Br, I, OH and _NH2 ;
Each R is independently H, F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkyl-(C=O)-NH-, C _1-3 alkyl- selected from O-(C=O)-NH-, C _3-6 cycloalkyl-(C=O)-NH- and C _1-6 alkyl-O-(C=O)-, said C _1-3 Alkyl, C _1-3 alkyl-(C=O)-NH-, C _3-6 cycloalkyl-(C=O)-NH- or C _1-6 alkyl-O-(C=O)- is selected optionally substituted by 1, 2 or 3 R',
each R' is independently selected from F, Cl, Br, I, OH and _NH2 ;
Said 5- to 6-membered heteroaryl, 5- to 10-membered heteroaryl and 5- to 9-membered heterocycloalkyl are each independently represented by 1, 2, 3 or 4 groups of -NH-, -C(=O)-, - Compounds, isomers or pharmaceutically acceptable salts thereof, containing a heteroatom or heteroatom group selected from O-, -S- and N are provided.

から選択され、ここで、前記Ｍｅ、Ｅｔ、

は、選択的に１、２または３個のＲ’によって置換され、本発明において定義されたとおりである。 In some embodiments of the present invention, R is F, Cl, Br, I, OH, _NH2 , Me, Et,

wherein said Me, Et,

is optionally substituted by 1, 2 or 3 R', as defined in the present invention.

から選択され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, R is F, Cl, Br, I, OH, _NH2 , Me,

and the other variables are as defined in the present invention.

In some embodiments of the present invention, each R _a is independently selected from H, F, Cl, Br, I, OH, _NH2 and Me.

In some embodiments of the present invention, said R ₁ is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, NH ₂ —(C═O)—CH ₂ —, isoindoline-1,3-dione —(CH ₂ ) ₂ —, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-diazacycloheptyl, —C _1-4 alkyl-phenyl, 2-azaspiro [3. 3]heptyl and 7-azaspiro[3.5]nonyl, said methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, NH ₂ —(C═O)—CH ₂ —, isoindoline-1, 3-dione-(CH ₂ ) ₂ -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-diazacycloheptyl, —C _1-4 alkyl-phenyl, 2-azaspiro [3.3]heptyl and 7-azaspiro[3.5]nonyl are optionally substituted by 1, 2 or 3 R, with other variables as defined herein.

から選択され、ここで、前記Ｍｅ、Ｅｔ、

は、選択的に１、２または３個のＲによって置換され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, said R ₁ is Me, Et,

wherein said Me, Et,

is optionally substituted by 1, 2 or 3 R and other variables are as defined herein.

から選択され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, said R ₁ is Me,

and the other variables are as defined in the present invention.

In some embodiments of the present invention, said _R2 and _R3 are each independently selected from H, F, Cl, Br, I, OH, _NH2 and Me, and the other variables of the present invention are as defined in

In some embodiments of the present invention, said _R4 is selected from H and Me, the other variables being as defined herein.

In some embodiments of the present invention, said Ring A is selected from furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl and phenyl, and said furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl and phenyl is optionally substituted by 1, 2 or 3 R _a , other variables are as defined herein.

から選択され、前記

は、選択的に１、２または３個のＲ_ａによって置換され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, said ring A is

is selected from the aforesaid

is optionally substituted by 1, 2 or 3 R _a , other variables are as defined herein.

から選択され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, said ring A is

and the other variables are as defined in the present invention.

から選択され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, in the compound, isomer thereof or pharmaceutically acceptable salt thereof, the structural unit

and the other variables are as defined in the present invention.

ここで、
環Ａは、５～６員ヘテロアリールから選択され、
Ｒ_１は、Ｃ_１－６アルキル、ＮＨ_２－（Ｃ＝Ｏ）－Ｃ_１－３アルキル－、５～１０員ヘテロアリール－Ｃ_１－３アルキル－、Ｃ_３－７シクロアルキル、５～６員ヘテロシクロアルキル、５～１０員ヘテロアリール、フェニルから選択され、前記Ｃ_１－６アルキル、ＮＨ_２－（Ｃ＝Ｏ）－Ｃ_１－３アルキル－、５～１０員ヘテロアリール－Ｃ_１－３アルキル－、Ｃ_３－７シクロアルキル、５～６員ヘテロシクロアルキル、５～１０員ヘテロアリール、フェニルは、選択的に１、２または３個のＲによって置換され、
Ｒは、それぞれ独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、ＮＨ_２、Ｃ_１－３アルキル、Ｃ_１－３アルキル－（Ｃ＝Ｏ）－ＮＨ－、Ｃ_１－３アルキル－Ｏ－（Ｃ＝Ｏ）－ＮＨ－、Ｃ_３－６シクロアルキル－（Ｃ＝Ｏ）－ＮＨおよびＣ_１－６アルキル－Ｏ－（Ｃ＝Ｏ）－から選択され、前記Ｃ_１－３アルキル、Ｃ_１－３アルキル－（Ｃ＝Ｏ）－ＮＨ－、Ｃ_３－６シクロアルキル－（Ｃ＝Ｏ）－ＮＨ－またはＣ_１－６アルキル－Ｏ－（Ｃ＝Ｏ）－は、選択的に１、２または３個のＲ’によって置換され、
Ｒ’は、それぞれ独立して、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、ＮＨ_２から選択され、
前記５～６員ヘテロアリール、５～１０員ヘテロアリールおよび５～６員ヘテロシクロアルキルは、１、２、３または４個のの独立的に－ＮＨ－、－Ｃ（＝Ｏ）－、－Ｏ－、－Ｓ－およびＮから選択されるヘテロ原子またはヘテロ原子団を含む、式（Ｉ）化合物、その異性体またはその薬学的に許容される塩をさらに提供する。 The present invention provides a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

here,
Ring A is selected from 5-6 membered heteroaryl,
R ₁ is C _1-6 alkyl, NH ₂ —(C═O)—C _1-3 alkyl-, 5-10 membered heteroaryl-C _1-3 alkyl-, C _3-7 cycloalkyl, 5-6 selected from membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, said C _1-6 alkyl, NH ₂ —(C═O)—C _1-3 alkyl-, 5-10 membered heteroaryl-C _{1- 3} alkyl-, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl optionally substituted by 1, 2 or 3 R,
Each R is independently H, F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkyl-(C=O)-NH-, C _1-3 alkyl- selected from O-(C=O)-NH-, C _3-6 cycloalkyl-(C=O)-NH and C _1-6 alkyl-O-(C=O)-, said C _1-3 alkyl , C _1-3 alkyl-(C=O)-NH-, C _3-6 cycloalkyl-(C=O)-NH- or C _1-6 alkyl-O-(C=O)- is optionally substituted by 1, 2 or 3 R' in
each R' is independently selected from F, Cl, Br, I, OH, _NH2 ;
Said 5- to 6-membered heteroaryl, 5- to 10-membered heteroaryl and 5- to 6-membered heterocycloalkyl are independently 1, 2, 3 or 4 -NH-, -C(=O)-, - Further provided are compounds of formula (I), isomers thereof or pharmaceutically acceptable salts thereof, which contain a heteroatom or heteroatom group selected from O--, --S-- and N.

から選択され、前記Ｍｅ、Ｅｔ、

は、選択的に１、２または３個のＲ’によって置換され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, R is F, Cl, Br, I, OH, _NH2 , Me, Et,

is selected from said Me, Et,

is optionally substituted by 1, 2 or 3 R' and other variables are as defined herein.

から選択され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, R is F, Cl, Br, I, OH, _NH2 ,

and the other variables are as defined in the present invention.

In some embodiments of the present invention, said R ₁ is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, NH ₂ —(C═O)—CH ₂ —, isoindoline-1,3-dione —(CH ₂ ) ₂ —, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, said methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, NH ₂ —(C= O)—CH ₂ —, isoindoline-1,3-dione-(CH ₂ ) ₂ —, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl is optionally 1, 2 or 3 are substituted by R and other variables are as defined in the present invention.

から選択され、前記Ｍｅ、Ｅｔ、

は、選択的に１、２または３個のＲによって置換され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, said R ₁ is Me, Et,

is selected from said Me, Et,

is optionally substituted by 1, 2 or 3 R and other variables are as defined herein.

から選択され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the present invention, said R ₁ is Me,

and the other variables are as defined in the present invention.

In some embodiments of the present invention, said ring A is selected from furyl and the other variables are as defined herein.

から選択され、他の変数は、本発明において定義されたとおりである。 In some embodiments of the invention, the structural unit

and the other variables are as defined in the present invention.

Some solutions of the present invention are derived from any combination of each of the above variables.

から選択され、
ここで、
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４および環Ａは、本発明で定義されたとおりであり、
「＊」が付いた炭素原子は、キラル炭素原子であり、（Ｒ）または（Ｓ）単一のエナンチオマー形態またはエナンチオマーに富んだ形態で存在する。 In some embodiments of the invention, the compound, its isomers or pharmaceutically acceptable salts are

is selected from
here,
R ₁ , R ₂ , R ₃ , R ₄ and Ring A are as defined herein;
Carbon atoms marked with an "*" are chiral carbon atoms and exist in (R) or (S) single or enantiomerically enriched forms.

から選択され、
ここで、
Ｒ_１、Ｒ_２、Ｒ_３およびＲ_４は、本発明で定義されたとおりであり、
「＊」が付いた炭素原子は、キラル炭素原子であり、（Ｒ）または（Ｓ）単一のエナンチオマー形態またはエナンチオマーに富んだ形態で存在する。 In some embodiments of the invention, the compound, its isomers or pharmaceutically acceptable salts are

is selected from
here,
R ₁ , R ₂ , R ₃ and R ₄ are as defined in the present invention;
Carbon atoms marked with an "*" are chiral carbon atoms and exist in (R) or (S) single or enantiomerically enriched forms.

から選択され、
ここで、
ｍは、０、１または２であり、
ｎは、１または２であり、
Ｒ_ａ、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４および環Ａは、本発明で定義されたとおりであり、
「＊」が付いた炭素原子は、キラル炭素原子であり、（Ｒ）または（Ｓ）単一のエナンチオマー形態またはエナンチオマーに富んだ形態で存在する。 In some embodiments of the invention, the compound, its isomers or pharmaceutically acceptable salts are

is selected from
here,
m is 0, 1 or 2;
n is 1 or 2,
R _a , R ₁ , R ₂ , R ₃ , R ₄ and Ring A are as defined herein;
Carbon atoms marked with an "*" are chiral carbon atoms and exist in (R) or (S) single or enantiomerically enriched forms.

The present invention further provides compounds of the following formula, isomers thereof, or pharmaceutically acceptable salts thereof.

から選択される。 In some embodiments of the invention, the compound, its isomers or pharmaceutically acceptable salts are

is selected from

から選択される。 In some embodiments of the invention, the compound, its isomers or pharmaceutically acceptable salts are

is selected from

The present invention further provides a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of said compound, an isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. do.

The present invention further provides use of said compound or a pharmaceutically acceptable salt thereof or said pharmaceutical composition in the preparation of a medicament for treating a CXCR2-related disease.

In some embodiments of the invention, the use is characterized in that the drug is a drug for treating COPD.

technical effect

The compounds of the invention have potent antagonistic effects on CXCR2, exhibit reduced clearance rates in mice, greatly improved plasma exposure, and greatly improved bioavailability compared to reference compounds. be.

Definition and explanation

Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A single specific term or phrase should not be considered uncertain or ill-defined, but should be understood in its ordinary sense, unless otherwise defined. When a trade name appears in this specification, it refers to the corresponding trade or its active ingredient. As used herein, the term "pharmaceutically acceptable" is within the scope of sound medical judgment, suitable for use in contact with human and animal tissue, and free from undue toxicity, irritation, allergy Refers to compounds, materials, compositions and/or dosage forms that are free of reactions or other problems or complications and are commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of compounds of this invention prepared from compounds having specific substituents found in this invention and relatively non-toxic acids or bases. Where a compound of the invention contains a relatively acidic functional group, a base addition salt can be formed by contacting the neutral form of such compound with a sufficient amount of base in neat solution or a suitable inert solvent. Obtainable. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound of the invention contains a relatively basic functional group, an acid addition salt is formed by contacting the neutral form of such compound with a sufficient amount of acid in neat solution or a suitable inert solvent. Obtainable. Illustrative pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, wherein said inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monophosphate. Hydrogen, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, etc., wherein said organic acids include acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, of pharmaceutically acceptable acid addition salts, including similar acids such as suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; Examples further include salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention can be converted into any base or acid addition salt by containing basic and acidic functional groups.

A pharmaceutically acceptable salt of the invention can be synthesized from a parent compound that contains an acid or base group by conventional chemical methods. Generally, such salts are prepared by reacting the compounds in the free acid or free base form with stoichiometric amounts of the appropriate base or acid in water or an organic solvent or a mixture of both. .

In addition to salt form, compounds provided by the present invention also exist in prodrug form. Prodrugs of the compounds described herein are readily chemically transformed under physiological conditions to compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are within the scope of the present invention.

The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention provides cis and trans isomers, (−)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and all compounds, including racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, are contemplated and are within the scope of the present invention. Additional asymmetric carbon atoms can be present in substituents such as alkyl. All these isomers and mixtures thereof are included within the scope of this invention.

Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

Unless otherwise stated, the terms "cis-trans isomer" or "geometric isomer" are caused by the inability of the double or single bonds of the ring-forming carbon atoms to rotate freely.

Unless otherwise stated, the term "diastereomers" refers to stereoisomers whose molecules possess two or more chiral centers and in which there is a non-mirror relationship between the molecules.

Unless otherwise stated, "(D)" or "(+)" denotes dextrorotation, "(L)" or "(-)" denotes left rotation, "(DL)" or "(±) ” stands for racemate.

およびくさび形の破線の結合

で立体中心の絶対構成を表し、直線の実線の結合

および直線の破線の結合

で立体中心の相対的な構成を表し、波線

でくさび形の実線の結合

またはくさび形の破線の結合

を表し、または波線

で直線の実線の結合

および直線の破線の結合

を表す。 Solid wedge-shaped joins unless otherwise stated

and the join of the wedge-shaped dashed lines

represents the absolute configuration of the stereocenter, and the solid straight line bond

and straight dashed join

represents the relative configuration of the stereocenter, and the wavy line

Wedge-shaped solid line join

or a wedge-shaped dashed join

or a squiggly line

Joining straight solid lines with

and straight dashed join

represents

The compounds of the invention can exist specifically. Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to the fact that at room temperature isomers of different functional groups are in dynamic equilibrium and can be rapidly converted into one another. Where tautomers are possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include proton transfer interconversions such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve several recombination of bond-forming electrons for interconversion. A specific example of keto-enol tautomerization here is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise specified, the terms “enriched in one isomer”, “enriched in isomer”, “enriched in one enantiomer” or “enriched in enantiomer” refer to a content of one isomer or enantiomer greater than 100%. less, the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, Or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

Unless otherwise stated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the excess isomer or enantiomer (ee value) is 80%.

Optically active (R)- and (S)- and D- and L-isomers may be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, the resulting mixture of diastereomers separated and the auxiliary cleaved to give a pure provide the desired enantiomer. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with a suitable optically active acid or base followed by The diastereomers are separated and the pure enantiomers recovered by conventional methods. In addition, separation of enantiomers and diastereomers is commonly performed using chromatography using chiral stationary phases, optionally coupled with chemical derivatization methods (such as carbamates formed from amines). The compounds of the present invention can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioisotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). As another example, hydrogen can be replaced with deuterium to form a deuterated drug, where the bond formed by deuterium and carbon is stronger than the bond formed by normal hydrogen and carbon, Compared with non-deuterated drugs, deuterated drugs have advantages such as less toxic side effects, improved drug stability, enhanced efficacy, and extended drug biological half-life. . All isotopic transformations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

"Optionally" or "optionally" means that the event or situation described below may, but does not necessarily, occur and the description includes the circumstances under which the event or situation does or does not occur means

The term "substituted" means that any one or more hydrogen atoms on a particular atom can be replaced by a substituent, so long as the valence state of the particular atom is normal and the compound after substitution is stable. , meaning that it can contain deuterium and hydrogen variants. When a substituent is oxygen (ie =O), it means that 2 hydrogen atoms are replaced. Oxygen substitution does not occur in aromatic groups. "Optionally substituted" means substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any chemically achievable. be.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, the definitions on each occasion are independent. Thus, for example, if a group is replaced with 0-2 R, then said group can optionally be replaced with up to 2 R, with R in each case having independent options. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

When the number of one linking group is 0, such as -(CRR) ₀ -, it means that the linking group is a single bond.

When a variable is selected from a single bond, it means that the two groups it is linked to are directly linked, for example, when L in ALZ represents a single bond, said The structure is actually implied to be AZ.

If one substituent is empty, it means that said substituent is absent, eg, if X is empty in AX, it means that the structure is actually A. Where no atom is indicated through which a listed substituent is attached to the substituted group, such substituent may be attached through any of those atoms. For example, pyridyl as a substituent can be attached to the substituted group through any carbon atom of the pyridine ring.

の結合基Ｌは－Ｍ－Ｗ－であり、このとき－Ｍ－Ｗ－は環Ａと環Ｂを左から右に読み順と同じ方向に連結して

を形成してもよいし、環Ａと環Ｂを左から右に読み順の逆方向に連結して

を形成してもよい。前記結合基、置換基、および／またはその変形の組み合わせは、そのような組み合わせが安定した化合物を生成する場合にのみ許可される。 If the listed linking group does not indicate the direction of linkage, the direction of linkage is arbitrary. for example,

The linking group L of is -MW-, where -MW- connects ring A and ring B in the same direction as the reading order from left to right

or concatenate ring A and ring B from left to right in reverse reading order to form

may be formed. Combinations of the above linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group of atoms containing a heteroatom) and includes atoms other than carbon (C) and hydrogen (H), and heteroatoms thereof. atomic groups such as oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, -C (=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and optionally substituted -C(= O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocyclenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl group. Said rings include monocyclic rings and also bicyclic or polycyclic ring systems such as spiro rings, fused rings, and bridged rings. The number of ring atoms is generally defined as the number of members in the ring, eg, a “5- to 7-membered ring” refers to 5-7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, a "5- to 7-membered ring" includes, for example, phenyl, pyridyl, and piperidinyl, while the term "5- to 7-membered heterocycloalkyl" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each "ring" independently conforming to the definitions above.

Unless otherwise stated, the term “alkyl” is used to denote a straight or branched chain saturated hydrocarbon group, in some embodiments said alkyl is a C _1-12 alkyl group, and in other embodiments In one aspect, the alkyl group is a C _1-6 alkyl group, and in another embodiment the alkyl group is a C _1-3 alkyl group. It can be monosubstituted (eg —CH ₂ F) or polysubstituted (eg —CF ₃ ), monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine ). Examples of alkyl include methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (n- pentyl, isopentyl, neopentyl), hexyl, and the like, but are not limited to these.

Unless otherwise specified, "alkenyl" is used to denote a straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds, wherein the carbon-carbon double bond can be any of the preceding groups. position can be located. In some embodiments, said alkenyl is C _2-8 alkenyl, in other embodiments said alkenyl is C _2-6 alkenyl, in other embodiments said alkenyl is C _{2- 4} alkenyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent. Examples of alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.

Unless otherwise stated, "alkynyl" is used to denote a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds, the carbon-carbon triple bond being at any position of the group. can be located. In some embodiments, said alkynyl is C _2-8 alkynyl, in other embodiments said alkynyl is C _2-6 alkynyl, in other embodiments said alkynyl is C _{2- 4} alkynyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

Unless otherwise specified, the term "heteroalkyl," by itself or in combination with another term, refers to a stable linear chain consisting of the specified number of carbon atoms and at least one heteroatom or heteroatom group or combinations thereof. or branched alkyl group or composition thereof. In some embodiments, heteroatoms are selected from B, O, N and S, wherein nitrogen and sulfur atoms are optionally oxidized and nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom group is -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N( H)-. In some embodiments, said heteroalkyl is C _1-6 heteroalkyl, and in other embodiments said heteroalkyl is C _1-3 heteroalkyl. The heteroatom or heteroatom group can be placed at any interior position of the heteroalkyl, including the point of attachment of the alkyl group to the rest of the molecule, except that the terms "alkoxy", "alkylamino" and ""Alkylthio" (or thioalkoxy) is a conventional expression that refers to those alkyl groups linked to the rest of the molecule via an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkyl are -OCH ₃ , -OCH ₂ CH ₃ , -OCH 2 CH ₂ CH ₃ , -OCH ₂ (CH ₃ ) ₂ , -CH ₂ -CH _{2 -O} -CH ₃ , -NHCH ₃ , - N( _CH3 ) ₂ , _-NHCH2CH3 , -N( _{CH3 )} (CH2CH3), -CH2 _{- CH2 - NH} - _CH3 , -CH2 _- CH2 _- N( _CH3 ) _-CH3 , _-SCH3 , _-SCH2CH3 , _-SCH2CH2CH3 , _-SCH2 ( _CH3 ) _{2 , -CH2 -} S- _CH2 - _CH3 , -CH2 _{- CH2 ,} -S(=O)-CH ₃ , -CH ₂ -CH ₂ -S(=O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , -CH ₂ -CH=N-OCH ₃ and -CH Including, but not limited to, ═CH—N(CH ₃ )—CH ₃ . Up to two heteroatoms, eg -CH2-NH-OCH3, can be consecutive.

Unless otherwise specified, the term "heteroalkenyl" by itself or in combination with another term means a stable linear chain consisting of the specified number of carbon atoms and at least one heteroatom or heteroatom group or combinations thereof. or a branched alkenyl group or composition thereof. In some embodiments, heteroatoms are selected from B, O, N and S, wherein nitrogen and sulfur atoms are optionally oxidized and nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom group is -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N( H)-. In some embodiments, said heteroalkenyl is C _2-6 heteroalkenyl, and in other embodiments, said heteroalkenyl is C _2-4 heteroalkenyl. The heteroatom or heteroatom group can be placed at any interior position of the heteroalkenyl, including the position of attachment of the alkenyl group to the rest of the molecule, except that the terms "alkenyloxy", "alkenylamino" and ""Alkenylthio" is a common expression and refers to those alkenyl groups linked to the rest of the molecule through an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkenyl are -O-CH=CH ₂ , -O-CH=CHCH ₃ , -O-CH=C(CH ₃ ) ₂ , -CH=CH-O-CH ₃ , -O-CH=CHCH ₂ CH ₃ , -CH ₂ -CH=CH-OCH ₃ , -NH-CH=CH ₂ , -N(CH=CH ₂ )-CH ₃ , -CH=CH-NH-CH ₃ , -CH=CH- N(CH ₃ ) ₂ , -S-CH=CH ₂ , -S-CH=CHCH ₃ , -S-CH=C(CH ₃ ) ₂ , -CH ₂ -S-CH=CH ₂ , -S(= O)-CH=CH ₂ and -CH=CH-S(=O) ₂ -CH ₃ , including but not limited to. Up to two heteroatoms, eg -CH=CH-NH-OCH ₃ can be consecutive.

を含むが、これらに限定されない。最大で２つのヘテロ原子、例えば

は連続であることができる。 Unless otherwise specified, the term "heteroalkynyl" by itself or in combination with another term means a stable linear chain consisting of the specified number of carbon atoms and at least one heteroatom or heteroatom group or combinations thereof. or a branched alkynyl group or composition thereof. In some embodiments, heteroatoms are selected from B, O, N and S, wherein nitrogen and sulfur atoms are optionally oxidized and nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom group is -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N( H)-. In some embodiments, said heteroalkynyl is C _2-6 heteroalkynyl, in other embodiments said heteroalkynyl is C _2-4 heteroalkynyl. The heteroatom or heteroatom group can be placed at any interior position of the heteroalkynyl, including the position of attachment of the alkynyl to the rest of the molecule, except that the terms "alkynyloxy", "alkynylamino" and ""Alkynylthio" is a common expression and refers to those alkynyl groups linked to the rest of the molecule through an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkynyls are

including but not limited to. up to two heteroatoms, e.g.

can be continuous.

Unless otherwise specified, "cycloalkyl" includes any stable cyclic alkyl including monocyclic, bicyclic, or tricyclic systems, where bicyclic and tricyclic systems are spirocycles, Includes fused rings and bridged rings. In some embodiments, said cycloalkyl is C _3-8 cycloalkyl, in other embodiments said cycloalkyl is C _3-6 cycloalkyl, in other embodiments said cycloalkyl is C _5-6 cycloalkyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent. Examples of these cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like. .

Unless otherwise specified, "cycloalkenyl" refers to any stable carbon-carbon double bond containing one or more unsaturated carbon-carbon double bonds at any position of the group, including monocyclic, bicyclic or tricyclic. cyclic alkenyls, where bicyclic and tricyclic ring systems include spiro, fused, and bridged rings, provided that any ring in the system is non-aromatic. In some embodiments, said cycloalkenyl is C _3-8 cycloalkenyl, in other embodiments said cycloalkenyl is C _3-6 cycloalkenyl, in other embodiments said cycloalkenyl is C _5-6 cycloalkenyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent. Examples of these cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

Unless otherwise specified, "cycloalkynyl" refers to any stable cyclic containing one or more carbon-carbon triple bonds at any position of said group, including monocyclic, bicyclic or tricyclic systems. Including alkynyl, bicyclic and tricyclic ring systems include spiro rings, fused rings, and bridged rings. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent.

Unless otherwise stated, the term “heterocycloalkyl” by itself or in combination with other terms means cyclized “heteroalkyl” including monocyclic, bicyclic and tricyclic systems, where two Cyclic and tricyclic systems include spiro rings, fused rings, and bridged rings. Additionally, for said "heterocycloalkyl," a heteroatom can occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. In some embodiments, said heterocycloalkyl is a 4-6 membered heterocycloalkyl, and in other embodiments said heterocycloalkyl is a 5-6 membered heterocycloalkyl. Examples of heterocycloalkyl include azetidine, oxetanyl, thietane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (tetrahydrofuran-2-yl, etc.). ), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.) ), dioxane, dithioalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxetanyl not.

を含むが、これらに限定されない。 Unless otherwise stated, the term "heterocyclenyl" by itself or in combination with other terms means a cyclized "heteroalkenyl" including monocyclic, bicyclic and tricyclic systems, bicyclic and tricyclic Ring systems include spiro rings, fused rings, and bridged rings, but any ring in the system is non-aromatic. Additionally, for said "heterocyclenyl" a heteroatom can occupy the position at which the heterocyclenyl is linked to the remainder of the molecule. In some embodiments, said heterocyclenyl is a 4-6 membered heterocyclenyl, and in other embodiments, said heterocyclenyl is a 5-6 membered heterocyclenyl. Examples of heterocyclenyls are

including but not limited to.

Unless otherwise specified, the term "heterocycloalkynyl" by itself or in combination with other terms means a cyclized "heteroalkynyl" including monocyclic, bicyclic and tricyclic systems, herein Bicyclic and tricyclic systems include spiro rings, fused rings, and bridged rings. Additionally, for said "heterocycloalkynyl", a heteroatom can occupy the position at which the heterocycloalkynyl is linked to the rest of the molecule. In some embodiments, said heterocycloalkynyl is a 4-6 membered heterocycloalkynyl, and in other embodiments, said heterocycloalkynyl is a 5-6 membered heterocycloalkynyl. Unless otherwise stated, the term "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Additionally, the term "haloalkyl," is meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. not. Examples of haloalkyl, unless otherwise specified, include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

"Alkoxy" represents alkyl as described above with the specified number of carbon atoms attached through an oxygen bridge, unless otherwise specified C _1-6 alkoxy is C ₁ , C ₂ , C ₃ , C ₄ , C Including ₅ and _C6 alkoxy. In some embodiments, an alkoxy group is C _1-3 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentyloxy.

Unless otherwise stated, the terms "aromatic ring" and "aryl" of the present invention can be used interchangeably, and "aromatic ring" or "aryl" refer to monocyclic, bicyclic or tricyclic systems wherein at least one ring is aromatic and the rings of said bicyclic and polycyclic systems are fused together. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent, in some embodiments said aryl is C _6-12 aryl, in other embodiments the aryl group is , C _6-10 aryl. Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.). Substituents for any one of the above noted aryl ring systems are selected from the acceptable substituents described in this invention.

Unless otherwise stated, the terms "heteroaryl ring" and "heteroaryl" of the present invention can be used interchangeably, the term "heteroaryl" being independently selected from B, N, O, and S refers to an aryl (or aromatic ring) containing 1, 2, 3, or 4 heteroatoms, which may be a monocyclic, bicyclic, or tricyclic system, wherein the nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined herein), optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally It can be oxidized (ie, NO and S(O) _p , where p is 1 or 2). A heteroaryl can be attached to the remainder of the molecule through a heteroatom. In some embodiments, said heteroaryl is a 5-10 membered heteroaryl, and in other embodiments, said heteroaryl is a 5-6 membered heteroaryl. Examples of said heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (N-imidazolyl, 2-imidazolyl, 4 -imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl) , 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazole, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purine, benzimidazolyl (including 2-benzimidazolyl, etc.), indolyl (5 -indolyl, etc.), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.), pyrazinyl , purines, and phenyloxazolyls, but are not limited to these. Substituents for any one of the above noted heteroaryl ring systems are selected from the acceptable substituents described in this invention.

Unless otherwise specified, the term "aralkyl" is intended to include groups in which aryl is attached to alkyl, and in some embodiments, said aralkyl is a C _6-10 aryl-C _1-4 alkyl group. Yes, in another embodiment, said aralkyl is C _6-10 aryl-C _1-2 alkyl. Examples of aralkyl include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like. "Aryloxy" and "arylthio" each represent groups in which an aralkyl carbon atom (e.g., methyl) is replaced with an oxygen or sulfur atom; in some embodiments, aryloxy is C _6-10 aryl- O—C _1-2 alkyl, in other embodiments aryloxy is C _6-10 aryl-C _1-2 alkyl-O—. In some embodiments, said arylthio is C _6-10 aryl-S—C _1-2 alkyl, and in other embodiments said arylthio is C _6-10 aryl-C _1-2 alkyl-S— is. Examples of aryloxy and arylthio include, but are not limited to, phenoxymethyl, 3-(1-naphthyloxy)propyl, phenylthiomethyl, and the like.

Unless otherwise specified, the term “heteroaralkyl” is intended to include groups in which heteroaryl is attached to alkyl, and in some embodiments, said heteroaralkyl is a 5-8 membered heteroaryl-C _{1 -4} alkyl, in another embodiment said heteroaralkyl is a 5-6 membered heteroaryl-C _1-2 alkyl. Examples of heteroaralkyl include, but are not limited to, pyrrolylmethyl, pyrazolylmethyl, pyridylmethyl, pyrimidinylmethyl, and the like. "Heteroaryloxy" and "Heteroarylthio" each represent groups in which a carbon atom (e.g., methyl) in heteroaralkyl is replaced with an oxygen or sulfur atom, and in some embodiments, said heteroaryloxy is , 5-8 membered heteroaryl-O—C _1-2 alkyl, and in other embodiments, heteroaryloxy is 5-6 membered heteroaryl-C _1-2 alkyl-O—. In some embodiments, said heteroarylthio is 5-8 membered heteroaryl-S—C _1-2 alkyl, and in other embodiments said heteroarylthio is 5-6 membered heteroaryl-C _{1 -2} alkyl-S-. Examples of heteroaryloxy and heteroarylthio include, but are not limited to, pyrroleoxymethyl, pyrazolylmethyl, 2-pyridyloxymethyl, pyrrolethiomethyl, pyrazolylmethyl, 2-pyridylthiomethyl, and the like.

Unless otherwise specified, C _n-n+m or C _n -C _n+m includes any case of n to n+m carbons. For example, C _1-12 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , and C ₁₂ , n to n+m for example, C _1-12 is C _1-3 , C _1-6 , C 1-9 , C _3-6 , C _3-9 , C _3-12 , _{C 6-9} , C _6-12 , and C _9-12 , etc. Similarly, n-membered to n+m-membered means that the number of atoms in the ring is from n to n+m, for example, a 3-12 membered ring has 3 members It means ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring. Also includes any range from n to n+m, for example, 3-12 members, 3-6 members, 3-9 members, 5-6 members, 5-7 members, 6-7 members, 6-8 members, and Including 6-10 members, etc.

The term "leaving group" refers to a functional group or atom that can be displaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups are triflate; chlorine, bromine, iodine; sulfonates such as methanesulfonate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate; , including acyloxy such as trifluoroacetoxy.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to protecting groups suitable to prevent side reactions at the amino nitrogen position. Representative amino-protecting groups are formyl; acyl, such as alkanoyl (eg, acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); benzyloxycarbonyl (Cbz) and 9-fluorenemethoxy. arylmethoxycarbonyl such as carbonyl (Fmoc); arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-di-(4′-methoxyphenyl)methyl; and trimethylsilyl (TMS) and tert-butyldimethylsilyl including, but not limited to, silyls such as (TBS). The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl groups. Representative hydroxy protecting groups are alkyl such as methyl, ethyl, t-butyl; acyl such as alkanoyl (eg acetyl); benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm ), arylmethyl such as diphenylmethyl (diphenylmethyl, DPM); and silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS).

The compounds of this invention are well known to those of skill in the art, including the specific embodiments listed below, embodiments formed by combination with other chemical synthetic methods, and equivalent alternatives well known to those of skill in the art. are prepared by various synthetic methods, and preferred embodiments include, but are not limited to, examples of the present invention.

The compounds of the present invention may have various uses or indications, including but not limited to the specific uses or indications listed in this application.

Solvents for use in the present invention are commercially available. The following abbreviations are used in the present invention: aq stands for water and HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate. , EDC represents N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, m-CPBA represents 3-chloroperoxybenzoic acid, eq represents equivalents, equivalents, CDI , represents carbonyldiimidazole, DCM represents dichloromethane, PE represents petroleum ether, DIAD represents diisopropylazodicarboxylate, DMF represents N,N-dimethylformamide, DMSO represents dimethylsulfoxide. , EtOAc represents ethyl acetate, EtOH represents ethanol, MeOH represents methanol, CBz represents the amine protecting group benzyloxycarbonyl, BOC represents the amine protecting group tert-butoxycarbonyl represents room temperature, O/N represents _overnight , THF represents tetrahydrofuran, Boc ₂ O represents di-tert-butyl dicarbonate, TFA represents trifluoroacetic acid, DIPEA represents diisopropylethylamine, SOCl ₂ represents thionyl chloride, CS ₂ represents carbon disulfide, TsOH represents p-toluenesulfonic acid, NFSI represents N-fluoro-N-(benzenesulfonyl)benzenesulfonamide, NCS represents 1-chloropyrrolidine-2,5-dione, n-Bu ₄ NF stands for tetrabutylammonium fluoride, iPrOH stands for 2-propanol, mp stands for melting point, LDA stands for lithium diisopropylamide, HPMC stands for hydroxypropyl methylcellulose, HPβCD stands for hydroxypropyl -β-cyclodextrin, Ms represents methanesulfonyl, FmocCl represents fluorenylmethoxycarbonyl chloride.

Compounds are named manually or with ChemDraw® software, and commercially available compounds use the supplier's catalog name.

The relationship between the percentage of neutrophils in the lung tissue of each animal group and the dose of compound is shown. The relationship between the percentage of neutrophils in the bronchoalveolar lavage fluid of each animal group and the dose of compound is shown. The relationship between the percentage of monocytes in the bronchoalveolar lavage fluid of each animal group and the dose of compound is shown.

EXAMPLES The present invention will be described in detail below with reference to Examples, which are not intended to limit the scope of the present invention. The present invention is described herein in detail and specific examples thereof are also disclosed, and various modifications and improvements may be made to the specific examples of the invention without departing from the spirit and scope of the invention. It will be clear to those skilled in the art that it is possible.

Fragment BB-1

Synthetic route:

Step 1: Synthesis of compound BB-1-2.

Chloroacetaldehyde (40% aqueous solution, 21.89 mL) was dissolved in 250 mL of water, NaHCO ₃ (11.8 g, 140.47 mmol) was added at 0 °C, and compound BB-1-1 (10 g, 89.19 mmol) was added little by little and reacted at 30° C. for 40 hours. After completion of the reaction, the pH was adjusted to 1 with 40% H ₂ SO ₄ , diluted with ethyl acetate (100 mL), and extracted with ethyl acetate (100 mL×3). The organic phases obtained were combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to obtain the crude product, which was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-40%) to obtain the desired compound BB-1-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50 (d, J = 1.5 Hz, 1H), 6.35 (d, J = 1.5 Hz, 1H), 2.71 (t, J = 6.0 Hz, 2H), 2.56 - 2.46 (m, 2H), 2.14 - 2.03 (m, 2H).

Step 2: Synthesis of compound BB-1-3.

Compound BB-1-2 (3.8 g, 27.91 mmol) was dissolved in 100 mL of methanol, anhydrous sodium acetate (2.78 g, 33.84 mmol) and hydroxylamine hydrochloride (2.92 g). , 41.99 mmol) was added and stirred overnight at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, 80 mL of water was added to the resulting residue, and the mixture was extracted with ethyl acetate (50 mL x 3). The obtained organic phases were combined and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was removed from the filtrate under reduced pressure to obtain the desired compound BB-1-3 crude product, which was used directly in the next reaction.

Step 3: Synthesis of compound BB-1.

Compound BB-1-3 (3.0 g, 19.85 mmol) was dissolved in 120 mL of methanol and NiCl ₂ .6H ₂ O (5.21 g, 21.92 mmol) and NaBH ₄ (7.45 g, 196.86 mmol) was added, and the mixture was stirred at 0° C. for 3 hours to react. After the reaction was completed, 10 mL of saturated NH ₄ Cl solution was added, diluted with 40 mL of ethyl acetate and extracted with ethyl acetate (50 mL×3). The obtained organic phases were combined and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was removed from the filtrate under reduced pressure to obtain the desired compound BB-1. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.39 - 7.32 (m, 1H), 6.23 (s, 1H), 3.97 (br s, 1H), 2.54 - 2 .38 (m, 2H), 2.09 (br d, J = 5.0 Hz, 1H), 1.96 - 1.87 (m, 1H), 1.77 - 1.65 (m, 2H) .

Fragment BB-2

Synthetic route:

Step 1: Synthesis of compound BB-2-2.

Compound BB-2-1 (50 g, 308.60 mmol) was dissolved in 300 mL of tert-butyl methyl ether and dissolved in 25 mL of water solution with the addition of 12.34 g of sodium hydroxide. Under an ice bath, pivaloyl chloride (39.07 g, 324.03 mmol, 39.87 mL) was added dropwise, maintaining the temperature of the reaction solution below 35°C. After completion of the reaction, 200 mL of ethyl acetate was added for dilution, followed by extraction with 100 mL of ethyl acetate. The extracted organic phase was washed with saturated saline (100 mL×2) and dried over anhydrous sodium sulfate. Filtration followed by concentration gave the desired product BB-2-2. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.45 (s, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.65 (dd, J = 2.5, 8 .8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 1.22 (s, 9H).

Step 2: Synthesis of compound BB-2.

Compound BB-2-2 (7.08 g, 28.76 mmol) was dissolved in 150 mL of THF, and n-butyllithium (2.5 M, 29 mL) was added dropwise at -60°C. After completion of the dropwise addition, the reaction solution was transferred to 0°C and stirred, and sulfur powder (1.84 g, 57.53 mmol) was added at -60°C after 15 minutes. The reaction was stirred overnight at room temperature. After completion of the reaction, 2N HCl (40 mL) was added to quench the reaction, diluted by adding 100 mL of ethyl acetate, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (80 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give BB-2 crude product, which was used directly in the next reaction.

Fragment BB-3

Synthetic route:

Step 1: Synthesis of compound BB-3.

Compound BB-3-1 (25 g, 124.22 mmol) was dissolved in 200 mL DCM and triethylamine (37.71 g, 372.65 mmol, 51.87 mL) was added dropwise at 0 °C. Then, under an ice bath, methanesulfonyl chloride (37.04 g, 323.35 mmol, 25.03 mL) was added dropwise and stirred at this temperature for 1 hour. After completion of the reaction, 100 mL of water was added to quench the reaction, the reaction was diluted with 100 mL of DCM and extracted with DCM (100 mL x 2). After combining the organic phases, it is dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained is separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-30%) to obtain the desired product. to obtain compound BB-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.74 (br s, 1H), 3.71 - 3.59 (m, 2H), 3.51 - 3.30 (m, 2H), 3. 17 (s, 1H), 3.07 (s, 3H), 2.04 - 1.90 (m, 2H), 1.84 (tdd, J = 4.3, 8.6, 12.9 Hz, 1H), 1.49(s, 9H).

Fragment BB-4

Synthetic route:

Step 1: Synthesis of compound BB-4-1.

Compound BB-2 (12.57 g, 52.00 mmol) was dissolved in 200 mL DMF, potassium carbonate (7.19 g, 52.00 mmol) and compound BB-3 (9.44 g, 33.00 mmol). 80 mmol) was added and stirred overnight at 80°C. After completion of the reaction, 150 mL of water was added to quench the reaction, 100 mL of ethyl acetate was added to dilute, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated with a chromatography column (eluent: ethyl acetate / petroleum ether = 0-10%) to give compound BB-4-1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (br d, J = 8.5 Hz, 1 H), 7.41 (br d, J = 8.3 Hz, 1 H), 3.85 ( br d, J = 12.5 Hz, 1H), 3.51 (br s, 1H), 2.91 (br s, 2H), 2.12 (br s, 1H), 1.83 (br s, 1H), 1.69 - 1.61 (m, 1H), 1.53 (s, 9H), 1.47 (s, 2H), 1.36 (br s, 9H).

Step 2: Synthesis of compound BB-4.

Compound BB-4-1 (6.10 g, 14.35 mmol) was dissolved in 150 mL of DCM and m-CPBA (85%, 17.48 g, 86.12 mmol) was added portionwise at -10 °C. The mixture was added and reacted by stirring at -10°C for 5 hours. After completion of the reaction, 100 mL of saturated sodium sulfite solution and 100 mL of saturated sodium bicarbonate solution were added. After diluting the mixture with 100 mL of DCM, it was extracted with DCM (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. The drying agent is filtered off, the filtrate is freed from the solvent under reduced pressure to obtain the crude product, which is separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-25%) to give the desired compound. BB-4 was obtained. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.85 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 4.24 (br s , 1H), 4.07 (br s, 1H), 3.57 (br s, 1H), 3.07 (br s, 1H), 2.71 (br t, J = 12.3 Hz, 1H) , 2.25 (br s, 1H), 2.03 - 1.80 (m, 3H), 1.54 (s, 9H), 1.38 (br s, 9H).

Fragment BB-5

Synthetic route:

Step 1: Synthesis of compound BB-5-2.

Chloroacetaldehyde (40% aqueous solution, 22.38 mL) and NaHCO ₃ (9 g, 107.13 mmol) were dissolved in 50 mL of water, and compound BB-5-1 (10 g, 89.18 mmol) was added at 0 °C. ) was added and reacted by stirring between 0-25° C. for 18 hours. After the reaction was completed, the pH was adjusted to 1 with 40% H ₂ SO ₄ , ethyl acetate was added for extraction (100 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-30%) to obtain the desired compound BB-5-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.17 - 2.24 (m, 2 H) 2.52 (dd, J = 7.28, 5.77 Hz, 2 H) 2.90 ( t, J = 6.27 Hz, 2 H) 6.69 (d, J = 2.01 Hz, 1 H) 7.34 (d, J = 2.01 Hz, 1 H).

Step 2: Synthesis of compound BB-5-3.

Compound BB-5-2 (1 g, 7.34 mmol), anhydrous sodium acetate (0.8 g, 9.76 mmol) and hydroxylamine hydrochloride (698.78 mg, 10.06 mmol) were mixed in 15 mL. Dissolved in methanol and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, 5 mL of ethyl acetate and 3 mL of water were added to the resulting residue, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with water (5 mL×2) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was removed from the filtrate under reduced pressure to obtain the desired compound BB-5-3 crude product, which was used directly in the next reaction.

Step 3: Synthesis of compound BB-5.

Compound BB-5-3 (400 mg, 2.65 mmol) was dissolved in 5 mL of methanol, NiCl ₂ .6H ₂ O (628.98 mg, 2.65 mmol) was added and the temperature was lowered to 0 °C. rice field. NaBH ₄ (1 g, 26.46 mmol) was added thereto little by little and stirred at 0° C. for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, diluted with 20 mL of ethyl acetate and 15 mL of water, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL×2), and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, the solvent was removed from the filtrate under reduced pressure to obtain the crude target compound BB-5, which was directly used in the next reaction. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 - 1.48 (m, 1 H) 1.72 - 1.77 (m, 1 H) 1.86 - 1.96 (m, 2 H) 2.37 - 2.57 (m, 2H) 3.73 - 3.90 (m, 1H) 6.31 (d, J = 1.76Hz, 1H) 7.16 - 7. 22 (m, 1 H).

Fragment BB-6

Synthetic route:

Step 1: Synthesis of compound BB-6-1.

BB-2 (12.00 g, 49.64 mmol) and 2-bromoisopropane (9.17 g, 74.56 mmol, 7.00 mL) were dissolved in 120 mL DMF and potassium carbonate (10 g , 72.35 mmol) was added and the mixture was stirred at 80° C. overnight. After completion of the reaction, 150 mL of water was added and extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with water (80 mL×3) and saturated brine (80 mL×3) in that order, and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration was separated by chromatography column (eluent: ethyl acetate/petroleum ether = 0-20%) to obtain compound BB-6-1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (d, J = 6.78 Hz, 6 H) 1.51 (s, 9 H) 3.80 (spt, J = 6.69 Hz , 1 H) 7.39 (d, J = 8.53 Hz, 1 H) 7.51 (d, J = 8.53 Hz, 1 H).

Step 2: Synthesis of compound BB-6.

Compound BB-6-1 (10 g, 35.23 mmol) was dissolved in 150 mL of DCM, m-CPBA (30.00 g, 147.77 mmol) was added at 0 °C and stirred at 0 °C for 1 h. After stirring and reacting, the mixture was heated to 30° C. and reacted for 5 hours. After completion of the reaction, saturated sodium sulfite solution was added at 0° C. until the potassium iodide starch test paper did not turn blue, and saturated sodium bicarbonate solution was added until pH>7, and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate (150 mL x 3), and the organic phases were combined, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the crude product obtained by concentration was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-30%) to obtain the desired compound BB-6. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (d, J = 6.78 Hz, 6 H) 1.54 (s, 9 H) 3.68 - 3.78 (m, 1 H) 7.50 (d, J = 8.28 Hz, 1 H) 7.84 (d, J = 8.53 Hz, 1 H).

Fragment BB-7

Synthetic route:

Step 1: Synthesis of compound BB-7.

BB-7-1 was used and synthesized to obtain BB-7, referring to the synthetic method of BB-1 Steps 2 and 3.

Fragment BB-8

Synthetic route:

Step 1: Synthesis of compound BB-8.

BB-8-1 was used and synthesized to give BB-8, referring to the synthetic method of BB-3 Step 1.

Fragment BB-9

Synthetic route:

Step 1: Synthesis of compound BB-9.
BB-9-1 was used and synthesized to give BB-9, referring to the synthetic method of BB-3 Step 1.

Fragment BB-10

Synthetic route:

Step 1: Synthesis of compound BB-10.

BB-10-1 was used and synthesized to give BB-10, referring to the synthetic method of BB-3 Step 1.

Fragment BB-11

Synthetic route:

Step 1: Synthesis of compound BB-11.

BB-11-1 was used and synthesized to obtain BB-11, referring to the synthetic method of BB-1 Steps 2 and 3. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 7.14 (d, J = 5.2 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 3.93 (br d , J = 5.6 Hz, 1H), 2.82 - 2.75 (m, 2H), 1.88 - 1.80 (m, 2H), 1.69 - 1.59 (m, 2H)

Fragment BB-12

Synthetic route:

Step 1: Synthesis of compound BB-12.

BB-12-1 was used and synthesized to obtain BB-12, referring to the synthetic method of BB-1 Steps 2 and 3. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 8.36 - 8.30 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 6 .4 Hz, 1H), 4.05 - 3.98 (m, 1H), 2.97 - 2.86 (m, 2H), 2.13 - 2.07 (m, 2H), 1.76 - 1.71 (m, 2H)

Fragment BB-13

Synthetic route:

Step 1: Synthesis of compound BB-13.

BB-13-1 was used and synthesized to obtain BB-13, referring to the synthesis method of BB-1 Steps 2 and 3.

Fragment BB-14

Synthetic route:

Step 1: Synthesis of compound BB-14.

Compound BB-14-1 (50 mg, 326.37 μmol) was dissolved in 5 mL of methanol and treated with ammonium acetate (251.57 mg, 3.26 mmol) and sodium cyanoborohydride (51.27 mg, 815 μmol). .92 μmol) was added and the reaction was heated to 80° C. and stirred for 16 hours. After completion of the reaction, the reaction solution was directly concentrated and dried to obtain a crude product. The crude product was separated and purified by preparative thin layer chromatography to give compound BB-14. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.97 (s, 1H), 4.51 (t, J = 5.6 Hz, 1H), 2.93 - 2.81 (m, 2H) , 2.28 - 2.18 (m, 1H), 2.14 - 2.03 (m, 1H), 1.94 (br d, J = 6.0 Hz, 2H)

Fragment BB-15

Synthetic route:

Step 1: Synthesis of compound BB-15-2.

Ceric ammonium nitrate (195.57 g, 356.74 mmol) was dissolved in methanol (400 mL) and treated at −35° C. under nitrogen protection with dimethoxypropene (38.58 g, 535.11 mmol) and compound BB- A solution of 15-1 (20 g, 178.37 mmol) in methanol (400 mL) was slowly added dropwise and stirred continuously for 0.5 hours. The reaction was then stirred at -35°C for 0.5 hours. After the reaction was complete, 400 mL of water and 80 mL of saturated sodium thiosulfate solution were added to quench the reaction. Concentrate under reduced pressure to remove methanol and extract the residue with ethyl acetate (750 mL x 2). The organic phases were combined, washed with saturated brine (750 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-25%) gave compound BB-15-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.18 (s, 1H), 3.70 - 3.64 (m, 2H), 2.55 - 2.50 (m, 2H), 2.40 - 2.35 (m, 2H), 2.21 (s, 3H), 2.03 - 1.97 (m, 2H).

Step 2: Synthesis of compound BB-15-3.

Compound BB-15-2 (9.90 g, 58.86 mmol) and divinylbenzene crosslinked sulfonated polystyrene (10 g) were dissolved in toluene (500 mL), and the reaction mixture was heated to 120° C. and stirred for 12 hours. bottom. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. Separation and purification by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-20%) gave compound BB-15-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.02 (s, 1H), 2.68 (t, J = 6.2 Hz, 2H), 2.54 - 2.47 (m, 2H), 2.34 (s, 3H), 2.13 - 2.06 (m, 2H).

Step 3: Synthesis of compound BB-15-4.

Compound BB-15-3 (380 mg, 2.53 mmol) was dissolved in methanol (15 mL) and sodium acetate (622.71 mg, 7.59 mmol) and hydroxylamine hydrochloride (351.67 mg, 5.5 mL) were added. 06 mmol) were added respectively and the reaction was stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness, 80 mL of ethyl acetate and 30 mL of water were added, thoroughly stirred, and allowed to stand still for liquid separation. The organic phase was washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound BB-15-4, which was directly followed by used for the reaction.

Step 4: Synthesis of compound BB-15-5.

Compound BB-15-4 (420 mg, 2.54 mmol) was dissolved in methanol (15 mL) and treated at 25° C. with nickel chloride hexahydrate (664.77 mg, 2.80 mmol) and sodium borohydride. (961.85 mg, 25.43 mmol) was added. The reaction solution was heated to 80° C. and stirred at 80° C. for 0.5 hours. After completion of the reaction, the reaction solution was concentrated to dryness, added with 80 mL of ethyl acetate and 50 mL of water, thoroughly stirred, filtered, and allowed to stand for liquid separation. The organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound BB-15-5, which was used directly in the next reaction. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.76 (s, 1H), 3.91 (br t, J = 5.6 Hz, 1H), 2.46 - 2.31 (m, 2H) , 2.25 (s, 3H), 2.07 - 2.01 (m, 1H), 1.88 - 1.77 (m, 1H), 1.74 - 1.66 (m, 2H), 1 .62-1.51 (m, 2H)

Step 5: Synthesis of compound BB-15.

Compound BB-15-5 (735 mg, 4.86 mmol) was dissolved in dichloromethane (50 mL) and sodium carbonate (618.25 mg, 5.83 mmol) and benzyl 4-nitrochloroformate (1.08 g , 5.35 mmol) were added respectively. The mixture was stirred at 25° C. for 0.5 hours. After completion of the reaction, water (50 mL) was poured into the reaction solution and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound intermediate BB-15, which was used directly in the next reaction without purification. board.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm (d, J = 9.2 Hz, 2H), 7.28 (d, J = 9.2 Hz, 2H), 5.75 (s, 1H), 5.34 (br d, J = 7.6 Hz, 1H), 4.84 - 4.73 (m, 1H), 2.43 - 2.27 (m, 2H), 2.20 (s, 3H ), 2.04 - 1.95 (m, 1H), 1.92 - 1.83 (m, 1H), 1.78 - 1.67 (m, 2H)

Fragment BB-16

Synthetic route:

Step 1: Synthesis of compound BB-16-2.

Compound BB-16-1 (20.00 g, 146.90 mmol) was dissolved in 1,2-dichloroethane (300 mL) and 1-trifluoromethyl-1,2-benzeneiodyl-3(H)- Ketone (51.06 g, 161.59 mmol), cuprous iodide (41.97 g, 220.35 mmol) were added. The reaction mixture was stirred at 60° C. for 14 hours to react. The reaction mixture was filtered, the filtrate was washed with saturated aqueous sodium bicarbonate solution (200 mL×2), filtered again, and the filtrate was extracted with dichloromethane (100 mL×2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (eluent: petroleum ether /ethyl acetate, 100:1-5:1) to give compound BB-16-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.80 (s, 1H), 2.83-2.79 (m, 2H), 2.65-2.61 (m, 2H), 2.24 -2.17 (m, 2H).

Step 2: Synthesis of compound BB-16-3.

Compound BB-16-2 (8.50 g, 41.64 mmol) was dissolved in anhydrous toluene (150 mL) and (R)-(−)-2-methyl-2-propanesulfinamide (7.57 g , 62.46 mmol) and tetraethyl titanate (28.49 g, 124.91 mmol) were added. The reaction mixture was stirred at 90° C. for 3 hours to react. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, the mixture was thoroughly stirred, filtered, and the filtrate was extracted with ethyl acetate (60 mL×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (eluent: petroleum ether /ethyl acetate, 10:1-1:1) to give compound BB-16-3.

Step 3: Synthesis of compound BB-16-4.

Compound BB-16-3 (8.30 g, 27.01 mmol) was dissolved in tetrahydrofuran (150 mL) and treated with diisobutylaluminum solution (1 M toluene solution, 41 mL, 40.0° C.) at 0° C. under nitrogen protection. 5 mmol) was slowly added dropwise. The reaction mixture was stirred at 0° C. for 1 hour to react. Water (200 mL) was added to the reaction solution to quench the reaction, and the mixture was thoroughly stirred, filtered, and the filtrate was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate, 10:1-1:1), to give compound BB-16-4.

Step 4: Synthesis of compound BB-16-5.

Compound BB-16-4 (6.20 g, 20.04 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), and concentrated hydrochloric acid (8 mL, 12N) was added dropwise at 0°C. The reaction mixture was stirred at 0° C. for 1 hour to react. The reaction mixture was adjusted to PH=8-9 with solid sodium carbonate aqueous solution, filtered, the filtrate was concentrated under reduced pressure, water (30 mL) was added to the residue, and extracted with dichloromethane (40 mL×2). . The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (eluent: dichloromethane/ methanol, 100:1-10:1), yielding compound BB-16-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.58 (s, 1H), 3.40-3.98 (m, 1H), 2.47-2.41 (m, 2H), 2.15 -2.11 (m, 1H), 1.89-1.86 (m, 1H), 1.74-1.65 (m, 2H).

Supercritical fluid chromatography analysis indicated that the two enantiomers had retention times of 1.785 minutes and 2.006 minutes, giving a ratio of 88.3:11.7.

Analytical conditions: Column: ChiralPak IC-3 150×4.6 mm I.D., 3 μm; mobile phase A: carbon dioxide B: ethanol (0.05% diethylamine); gradient from 5% in 5.5 min. 40% B, then 5% B in 1.5 min; flow rate: 2.5 mL/min; column temperature: 40° C.; detection wavelength: 220 nm.

Step 5: Synthesis of compound BB-16.

Compound BB-16-5 (300 mg, 1.46 mmol) was dissolved in dichloromethane (10 mL), sodium carbonate (232.46 mg, 2.19 mmol) and benzyl 4-nitrochloroformate (265.25 mg). , 1.32 mmol) were added respectively. The mixture was stirred at 20° C. for 1 hour. After completion of the reaction, the reaction solution was diluted with dichloromethane (40 mL) and washed with water (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was separated and purified by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-20%) to give compound intermediate BB-16.

Fragment BB-17

Synthetic route:

Step 1: Synthesis of compound BB-17-1.

Fragment BB-16-3 was synthesized from compound BB-16-2 to give compound BB-17-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.76 (s, 1H), 3.27-3.21 (m, 1H), 3.12-3.06 (m, 1H), 2.72 -2.69 (m, 2H), 2.09-2.03 (m, 2H), 1.32 (s, 9H).

Step 2: Synthesis of compound BB-17-2.

Compound BB-17-1 (0.35 g, 1.14 mmol) was dissolved in tetrahydrofuran (2 mL) and treated with sodium borohydride (86.2 mg, 2.28 mmol) at 0° C. under nitrogen protection. ) was added. The reaction mixture was stirred at 26° C. for 1 hour to react. Saturated saline (30 mL) was added to the reaction solution to quench the reaction, and the reaction system was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound BB-17-2, which was directly used in the next reaction. Using.

Step 3: Synthesis of compound BB-17-3.

Fragment BB-16-5 was synthesized from compound BB-17-2 to give compound BB-17-3.

Step 4: Synthesis of compound BB-17.

Compound BB-17 was obtained by synthesizing from compound BB-17-3 following the procedure for fragment BB-16.

Fragment BB-18

Synthetic route:

Step 1: Synthesis of compound BB-18-2.

Compound BB-18-1 (1.10 g, 2.41 mmol) was dissolved in toluene (10 mL), concentrated hydrochloric acid (12 M, 4.01 mL) was added to the reaction solution, and the mixture was heated to 80 °C. Heat and stir for 12 hours. The reaction was monitored for completion by thin layer chromatography and liquid chromatography. The reaction was then concentrated to give a crude brown solid BB-18-2.

Step 2: Synthesis of compound BB-18.

The above compound BB-18-2 (0.70 g, 2.41 mmol) was dissolved in dichloromethane (10 mL), then saturated NaHCO ₃ solution was added to adjust the solution to pH >7, and the solution was cooled at 0 °C. At the bottom, FmocCl (465.81 mg, 1.44 mmol) was added and the mixture was stirred at 25° C. for 1 hour. The reaction was monitored for completion by thin layer chromatography and liquid chromatography. The reaction solution was separated into layers, the aqueous phase was extracted three times with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography. (SiO ₂ , petroleum ether/ethyl acetate=3/1), BB-18 was obtained. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.47 (br s, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.55 (br d, J = 7.2 Hz, 2H), 7.44 - 7.38 (m, 2H), 7.37 - 7.29 (m, 2H), 6.87 (br d, J = 8.0 Hz, 1H), 6. 78 (br s, 1H), 4.43 (br s, 2H), 4.21 (br s, 1H), 4.02 (br s, 2H), 3.73 (br s, 1H), 3. 37 - 2.99 (m, 1H), 2.88 - 2.77 (m, 1H), 2.15 (br s, 1H), 1.99 - 1.78 (m, 2H), 1.32 - 1.19 (m, 1H)

Fragment BB-19

Synthetic route:

Step 1: Synthesis of compound BB-19-2.

Compound BB-19-1 (0.6 g, 4.08 mmol) was dissolved in methanol (20 mL), sodium acetate (1.00 g, 12.23 mmol) and hydroxylamine hydrochloride (424.95 mg, 6.12 mmol) were added respectively and the reaction was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction was quenched by adding 20 mL of saturated sodium bicarbonate solution, concentrated under reduced pressure to remove methanol, and extracted with dichloromethane (30 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound BB-19-2, which was used directly in the next reaction.

Step 2: Synthesis of compound BB-19.

Compound BB-19-2 (440 mg, 2.71 mmol) was dissolved in methanol (35 mL) and wet palladium on carbon (50 mg, 10% purity) was added. The reaction was placed under an atmosphere of hydrogen (50 PSI) and stirred at 25° C. for 16 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude compound BB-19, which was directly used in the next reaction.

¹ H NMR (400 MHz, METHANOL- _d4 ) δ ppm 8.32 (br d, J = 4.4 Hz, 1 H), 7.50 (br d, J = 7.6 Hz, 1 H), 7.16 (m, 1H), 4.02 - 3.89 (m, 1H), 2.84 - 2.74 (m, 2H), 2.11 - 1.91 (m, 2H), 1.82 - 1 .67 (m, 2H)

Fragment BB-20

Synthetic route:

Step 1: Synthesis of compound BB-20-2.

Under room temperature conditions, BB-20-1 (2.00 g, 18.00 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), pyridine (2.85 g, 35.99 mmol) and chloroacetyl ( 2.83 g, 35.99 mmol) were added respectively. The reaction solution was heated to 60° C. and stirred for 2 hours to react. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=0:1, dichloromethane/methanol=20:1) to give compound BB. -20-2 was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.82 (br.s, 1H), 6.59 (s, 1H), 2.60-2.56 (m, 2H), 2.39-2 .35 (m, 2H), 2.15 (s, 3H), 2.07-2.02 (m, 2H).

Step 2: Synthesis of compound BB-20-3.

Compound BB-20-2 (1.00 g, 6.53 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL) under 0° C. conditions, and N-bromosuccinimide (1.39 g, 7.83 mmol) was added. The reaction solution was heated to 25° C. and stirred for 4 hours to react. Water (30 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/acetic acid ethyl, 3:1-1:1), to give compound BB-20-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.95 (s, 1H), 3.27-3.23 (m, 2H), 2.61-2.57 (m, 2H), 2.23 (s, 3H), 2.07-2.00 (m, 2H).

Step 3: Synthesis of compound BB-20-4.

Compound BB-20-3 (1.20 g, 5.17 mmol) was dissolved in anhydrous dioxane (15 mL), cesium carbonate (3.54 g, 10.86 mmol), cuprous iodide (196 mg , 1.03 mmol) and dimethylglycine hydrochloride (433 mg, 3.10 mmol) were added. The reaction solution was heated to 90° C. and stirred for 3 hours to react. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100:1-40:1) to obtain compound BB-20-4. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.85-2.82 (m, 2H), 2.61-2.54 (m, 5H), 2.22-2.15 (m, 2H) .

Step 4: Synthesis of compound BB-20-5.

Compound BB-20-4 (540 mg, 3.57 mmol) was dissolved in anhydrous toluene (10 mL) and treated with 2-methyl-2-propanesulfinamide (563 mg, 4.64 mmol) and tetraethyl titanate (2 .44 g, 10.72 mmol) was added. The reaction mixture was stirred at 100° C. for 3 hours to react. Water (30 mL) and ethyl acetate (30 mL) were added to the reaction mixture, the mixture was thoroughly stirred, filtered, and the filtrate was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100:1-40:1) to give compound BB-20-5.

Step 5: Synthesis of compound BB-20-6.

Compound BB-20-5 (570 mg, 2.24 mmol) was dissolved in anhydrous methanol (10 mL), and sodium borohydride (84 mg, 2.24 mmol) was added at 0°C. . The reaction solution was stirred at 40° C. for 1 hour. Water (2 mL) was added to the reaction mixture to quench the reaction and concentrated under reduced pressure to give crude compound BB-20-6.

Step 6: Synthesis of compound BB-20.

Compound BB-20-6 (580 mg, 2.26 mmol) was dissolved in methanol (5 mL) and concentrated hydrochloric acid (1 mL, 12N) was added. The reaction mixture was stirred at 25° C. for 0.5 hours to react. Adjust the reaction solution to PH=8-9 with solid sodium carbonate, filter, concentrate the filtrate under reduced pressure, add dichloromethane/methanol=10:1 (30 mL) to the residue, stir for 3 minutes, After filtration, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 50:1-20:1) to obtain compound BB-20. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.00-3.97 (m, 1H), 2.50-2.41 (m, 5H), 2.11-2.08 (m, 1H) , 1.87-1.84 (m, 1H), 1.75-1.72 (m, 1H), 1.63-1.56 (m, 3H).

Fragment BB-21

Synthetic route:

Step 1: Synthesis of compound BB-21-2.

Compound BB-21-1 (10 g, 89.19 mmol) was dissolved in dichloromethane (200 mL) and liquid bromine (14.25 g, 89.19 mmol, 4.60 mL) was dissolved in dichloromethane (150 mL) at 0 °C. mL) solution was slowly added dropwise, lasting 30 minutes. After completion of dropping, the reaction solution was stirred at 25° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness to obtain a crude product, which was separated and purified by high-performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-20%) to give compound BB-21- got 2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.41 (s, 1H), 2.88 (t, J = 6.0 Hz, 2H), 2.61 - 2.54 (m, 2H), 2.13-2.02 (m, 2H)

Step 2: Synthesis of compound BB-21-3.

A solution of compound BB-21-2 (1 g, 5.23 mmol) and thioacetamide (393.32 mg, 5.23 mmol) in ethanol (30 mL) was heated to 90° C. and stirred for 12 hours. After completion of the reaction, the reaction mixture was concentrated to dryness to obtain a crude product, which was separated and purified by high-performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-40%) to give compound BB-21. -3 was obtained. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.05 (t, J = 6.0 Hz, 2H), 2.70 (s, 3H), 2.67 - 2.61 (m, 2H), 2.28-2.20 (m, 2H)

Step 3: Synthesis of compound BB-21.

Compound BB-21-3 (170 mg, 1.02 mmol) was dissolved in methanol (20 mL), ammonium acetate (783.58 mg, 10.17 mmol) and sodium cyanoborohydride (319.41 mg, 5.08 mmol) were added respectively. The reaction solution was heated to 80° C. and stirred for 12 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain a crude product, which was separated and purified by high-performance preparative chromatography (eluent: methanol/dichloromethane = 0 to 10%) to obtain compound BB-21. rice field. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 4.43 - 4.35 (m, 1H), 3.35 (s, 3H), 2.86 - 2.79 (m, 2H), 2.33 - 2.23 (m, 1H), 2.13 - 2.04 (m, 1H), 1.92 - 1.82 (m, 2H)

Fragment BB-22

Synthetic route:

Step 1: Synthesis of compound BB-22-2.

At 25 °C, sodium hydroxide (5.14 g, 128.41 mmol) was dissolved in water (150.00 mL), compound BB-22-1 (18 g, 128.41 mmol) was added, and the mixture was heated to 100 °C. for 2 hours. Extracted with ethyl acetate (200 mL x 2), washed the organic phase with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated and subjected to flash silica gel column chromatography (petroleum ether/acetic acid Ethyl 100-75%) and purified to give compound BB-22-2.

Step 2: Synthesis of compound BB-22-3.

At 25° C., sulfuric acid (3.18 g, 32.42 mmol) was dissolved in water (150.00 mL) and compound BB-22-2 (5.00 g, 32.42 mmol) was added to tetrahydrofuran (50.42 mmol). 00 mL) solution was added and reacted at 100° C. for 48 hours. Extracted with ethyl acetate (50 mL x 2), washed the organic phase with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated and subjected to flash silica gel column chromatography (petroleum ether/acetic acid Ethyl 100-83%) and purified to give compound BB-22-3. 1H NMR (400 MHz, CDCl3) δ ppm 6.00 (m, 1H), 5.90 (s, 1H), 2.40 (s, 2H), 2.30 (m, 2H), 1.09 (s , 6H)

Step 3: Synthesis of compound BB-22-4.

Chloroacetaldehyde (1.79 g, 9.12 mmol) and sodium bicarbonate (0.72 g, 8.56 mmol) were dissolved in water (20.00 mL) at 25 °C and compound BB- A solution of 22-3 (1.00 g, 7.13 mmol) in methanol (10.00 mL) was added and reacted at 25° C. for 60 hours. Dilute with ethyl acetate (10 mL), adjust pH=1 with 10% aqueous sulfuric acid, extract with ethyl acetate (10 mL×2), wash organic phase with saturated brine (20 mL), dry Dried over sodium sulfate, filtered, concentrated, separated and purified by thin layer silica gel chromatography (petroleum ether/ethyl acetate=80%) to give compound BB-22-4.

Step 4: Synthesis of compound BB-22-5.
BB-22-4 (733 mg, 4.46 mmol) and tert-butylsulfinamide (0.65 g, 5.36 mmol) were dissolved in toluene (10.00 mL) at 25° C. and the compound tetraethyl titanyl oxide (5.09 g, 22.32 mmol) was added and reacted at 110° C. for 16 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL x 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. , and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-75%) to give compound BB-22-5.

Step 5: Synthesis of compound BB-22-6.

Compound BB-22-6 was synthesized from compound BB-22-5 following the procedure for fragment BB-20-6.

Step 6: Synthesis of compound BB-22.

Compound BB-22 was obtained by synthesizing from compound BB-22-6 following the procedure for fragment BB-20. ¹ H NMR (400 MHz, CDCl3) δ ppm (d, J = 1.2 Hz, 1 H), 6.17 (d, J = 1.6 Hz, 1 H), 3.89 (m, 1 H), 2.34 (m, 1H), 2.22 - 2.13 (m, 1H), 1.88 (m, 1H), 1.37 (m, 1H), 1.09 (s, 3H), 0.93 ( s, 3H)

Fragment BB-23

Synthetic route:

Step 1: Synthesis of compound BB-23-2.

Compound BB-23-1 (9 g, 64.22 mmol) was dissolved in carbon tetrachloride (400 mL), N-bromosuccinimide (11.43 g, 64.22 mmol), azobisisobutyronitrile ( 1.05 g, 6.42 mmol) was added, purged with nitrogen three times, and the reaction mixture was allowed to react at 75° C. for 3 hours. After detecting the completion of the reaction by thin layer chromatography, dichloromethane (300 mL) and deionized water (300 mL) were added to the reaction mixture, the organic phase was separated, washed with brine (100 mL) and treated with anhydrous sulfuric acid. Dried over sodium, filtered and concentrated to give BB-23-2 which was used directly in the next reaction.

Step 2: Synthesis of compound BB-23-3.

Compound BB-23-2 (13 g, 59.35 mmol) was dissolved in N,N-dimethylformamide (200 mL) and ethyl 2-(methylamino)acetate hydrochloride (9.12 g, 59.35 mmol), potassium carbonate (24.61 g, 178.06 mmol) was added and the reaction mixture was allowed to react at 25° C. for 2 hours, the reaction was detected to be complete by thin layer chromatography, and ethyl acetate (500 mL) was added to the reaction mixture. ), deionized water (500 mL) was added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether/acetic acid ethyl=5:1-1:1) to give BB-23-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50 (d, J = 2.0 Hz 1 H), 6.66 (d, J = 1.6 Hz 1 H), 4.19 (q , J = 14.4 Hz, 2 H), 3.93 (s, 2 H), 3.90 (s, 3 H), 3.28 (s, 2 H), 2.41 (s, 3 H ), 1.28 (t, J = 7.2 Hz, 3 H).

Step 3: Synthesis of compound BB-23-4.

Compound BB-23-3 (10 g, 39.17 mmol) was dissolved in tetrahydrofuran (300 mL), the mixture was cooled to −78° C. and potassium tert-butoxide (8.79 g, 78.35 mmol) was added. Dissolved in tetrahydrofuran (100 mL), slowly added dropwise to the above reaction mixture, reacted at −78° C. for 14 hours, the completion of the reaction was detected by thin layer chromatography, and diluted hydrochloric acid (1M, 78 mL) was added to the reaction mixture. Saturated ammonium chloride (200 mL), ethyl acetate (500 mL) were added and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give BB-23-4. .

Step 4: Synthesis of compound BB-23-5.

Dilute hydrochloric acid (1 M, 100 mL) was added to compound BB-23-4 (4 g, 17.92 mmol), the reaction mixture was heated to 100° C. and allowed to react for 6 hours, and the completion of the reaction was detected by thin layer chromatography. , saturated sodium carbonate (20 mL), dichloromethane (100 mL) were added to the reaction mixture, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give BB-23- ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.62 (d, J = 1.6 Hz 1 H), 6.44 (d, J = 1.6 Hz 1 H), 3.70 (s, 2 H) , 3.30 (s, 2 H), 2.52 (s, 3 H).

Step 5: Synthesis of compound BB-23-6.

Compound BB-23-5 (1 g, 6.62 mmol) was dissolved in ethanol (30 mL), sodium acetate (1.09 g, 13.23 mmol) was added, and the reaction mixture was reacted at 80° C. for 12 hours. let me After detecting the completion of the reaction by thin layer chromatography, dichloromethane (100 mL), deionized water (50 mL) were added to the reaction mixture, the organic phase was separated, washed with saturated brine (20 mL), and anhydrous sulfuric acid was added. Dried over sodium, filtered and concentrated to give BB-23-6. ¹ H NMR (400 MHz, CD3OD) δ ppm 7.55 (d, J = 2.0 Hz 1 H), 6.47 (d, J = 2.0 Hz, 1 H), 3.69 (s, 2 H), 3.60 (s, 2 H), 2.53 (s, 3 H).

Step 6 : Synthesis of compound BB-23.
Compound BB-23-6 (0.25 g, 1.50 mmol) was dissolved in tetrahydrofuran (30 mL), lithium tetrahydroaluminum (285.50 mg, 7.52 mmol) was added, and the reaction was heated to 80°C. and reacted for 2 hours, detecting completion of the reaction by thin layer chromatography, adding deionized water (10 mL), tetrahydrofuran (10 mL) to the reaction mixture, filtering the mixture through celite and concentrating to give the crude product. The crude product was purified by column chromatography to give BB-23. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 (d, J = 1.2 Hz 1 H), 6.18 (d, J = 1.6 Hz 1 H), 3.96 (s, 1 H), 3.46-3.42 (m, 1 H), 3.21-3.17 (m, 1 H).
2.82-2.78 (m, 1 H), 2.63-2.59 (m, 1 H), 2.46 (s, 3 H).

Fragment BB-24

Synthetic route:

Step 1: Synthesis of compound BB-24-3.

Compound BB-24-2 (10.00 g, 45.90 mmol) was dissolved in toluene (400 mL), then compound BB-24-1 (11.03 g, 45.90 mmol), triethylamine (19 .16 mL, 137.69 mmol) was added to the reaction and the mixture was heated to 120° C. and stirred for 12 hours. Completion of the reaction was detected by thin layer chromatography. After that, the reaction mixture was concentrated, water (30 mL) and ethyl acetate (30 mL) were added, the aqueous phase was extracted three times with ethyl acetate (30 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate. filtered, concentrated and purified by column chromatography (dichloromethane/methanol=20/1) to give BB-24-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.36 - 7.26 (m, 10H), 3.85 - 3.77 (m, 1H), 3.75 - 3.62 (m, 4H) , 2.94 - 2.80 (m, 4H), 2.79 - 2.68 (m, 2H), 2.53 - 2.41 (m, 2H)

Step 2: Synthesis of compound BB-24-4.

Compound BB-24-3 (8.10 g, 27.33 mmol) was dissolved in methanol (300 mL), palladium hydroxide on carbon (2.00 g) was added to the reaction and the mixture was subjected to a hydrogen atmosphere of 15 psi. The mixture was stirred at room temperature for 3 hours. The reaction was detected to be complete by thin layer chromatography, the reaction was filtered through celite at room temperature to remove the catalyst, and the filtrate was spin dried to give crude compound BB-24-4.

Step 3: Synthesis of compound BB-24-5.

Compound BB-24-4 (2.60 g, 22.38 mmol) was dissolved in methanol (26 mL), triethylamine (7.48 mL, 53.72 mmol), Boc ₂ O (9.77 g, 44 .77 mmol) was added and the mixture was stirred at 25° C. for 1 hour. The completion of the reaction was detected by thin layer chromatography and liquid chromatography, the reaction was concentrated at room temperature, quenched with water (20 mL), extracted with dichloromethane (20 mL x 3), the organic layers were combined, and anhydrous sodium sulfate was added. , filtered, concentrated and purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give BB-24-5. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.31 - 4.08 (m, 1H), 4.03 - 3.86 (m, 3H), 3.86 - 3.54 (m, 1H) , 3.54 - 3.27 (m, 2H), 3.12 - 3.11 (m, 1H), 3.03 (m, 1H), 2.78 (m, 1H), 1.48 (s , 9H), 1.47 (s, 9H).

Step 4: Synthesis of compound BB-24.

Compound BB-24-5 (1.00 g, 3.16 mmol) was dissolved in dichloromethane (10 mL), triethylamine (1.10 mL, 3.90 mmol), DMAP (193.06 mg, 1.58 mmol) and p-toluenesulfonyl chloride (1.21 g, 6.32 mmol) were sequentially added to the reaction solution at 0° C., and the mixture was warmed to 40° C. and stirred for 1 hour. The completion of the reaction was detected by thin layer chromatography, the mixture was quenched with water (20 mL) at room temperature, extracted with dichloromethane (20 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate. , filtered, concentrated and purified by column chromatography (petroleum ether/ethyl acetate=7:3) to give compound BB-24. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 7.88 - 7.75 (m, 2H), 7.36 (br d, J = 7.2 Hz, 2H), 4.79 - 4.57 ( m, 1H), 3.88 - 3.27 (m, 8H), 2.46 (s, 3H), 1.52 - 1.38 (m, 18H).

Fragment BB-25

Synthetic route:

The above compound WX001-1 (0.70 g, 2.41 mmol) was dissolved in dichloromethane (10 mL), then saturated NaHCO ₃ solution was added to adjust the solution pH>7, and the temperature was kept at 0 °C. , FmocCl (465.81 mg, 1.44 mmol) was added and the mixture was stirred at 25° C. for 1 hour. The reaction was monitored for completion by thin layer chromatography and liquid chromatography. The reaction solution was separated into layers, the aqueous phase was extracted three times with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography ( SiO ₂ , petroleum ether/ethyl acetate=3/1), BB-25 was obtained. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.47 (br s, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.55 (br d, J = 7.2 Hz, 2H), 7.44 - 7.38 (m, 2H), 7.37 - 7.29 (m, 2H), 6.87 (br d, J = 8.0 Hz, 1H), 6. 78 (br s, 1H), 4.43 (br s, 2H), 4.21 (br s, 1H), 4.02 (br s, 2H), 3.73 (br s, 1H), 3. 37 - 2.99 (m, 1H), 2.88 - 2.77 (m, 1H), 2.15 (br s, 1H), 1.99 - 1.78 (m, 2H), 1.32 - 1.19 (m, 1H)

Fragment BB-26

Synthetic route:

Step 1: Synthesis of compound BB-26-1.

At 25° C., compound BB-2-2 (50.00 g, 203.14 mmol) was dissolved in tetrahydrofuran (500.00 mL), cooled to −25° C., and treated with n-butyllithium under the protection of nitrogen. (2.5 M, 138.14 mL, 345.34 mmol) was added dropwise, the internal temperature was kept below -10°C during the dropwise addition, and the reaction was allowed to proceed at -10°C for 5 minutes after the dropwise addition. Next, a solution of iodine (103.12 g, 406.29 mmol) in tetrahydrofuran (250.00 mL) was added dropwise. reacted for a minute. Saturated aqueous sodium thiosulfate solution (200 mL) was added to quench, extracted with ethyl acetate (200 mL x 2), the organic phase was washed with saturated aqueous sodium thiosulfate solution (200 mL), saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-96%) to give compound BB-26-1. Obtained.

Step 2: Synthesis of compound BB-26.

At 25° C., compound BB-26-1 (10.00 g, 29.80 mmol), cuprous iodide (1.14 g, 5.96 mmol), 1,10-fololine (1.07 g, 5.96 mmol) and potassium thioacetate (6.81 g, 59.60 mmol) were dissolved in toluene (100.00 mL) and reacted under nitrogen protection at 90° C. for 20 hours. After cooling to room temperature, water (100 mL) was added to quench, ethyl acetate (100 mL) was added to dilute, filtered, extracted with ethyl acetate (200 mL x 2), and the organic phase was washed with saturated sodium chloride. Washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-94%) to give compound BB-26. got

Fragment BB-27

Synthetic route:

Step 1: Synthesis of compound BB-27-2.

Compound BB-27-1 (83.79 g, 429.57 mmol) was dissolved in ethanol (500 mL), potassium carbonate (69.66 g, 504.00 mmol), potassium iodide (836.65 mg, 5.04 mmol) and benzylamine (54.00 g, 504.00 mmol) respectively were added and the mixture was heated to 85° C. and stirred for 16 hours. After completion of the reaction, the precipitated solid was removed by filtration under reduced pressure, and the filtrate was collected. The filtrate was concentrated under reduced pressure, separated and purified by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-20%) to obtain compound BB-27-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.38 - 7.26 (m, 5H), 4.20 (q, J = 7.2 Hz, 2H), 3.62 (s, 2H), 1.37 (s, 6H), 1.31 (t, J = 7.2Hz, 3H)

Step 2: Synthesis of compound BB-27-3.

A mixture of compound BB-27-2 (25.3 g, 114.33 mmol), ethyl bromobutyrate (23.41 g, 120.04 mmol) and potassium iodide (948.93 mg, 5.72 mmol) was Heated to 120° C. and stirred for 24 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (250 mL). The precipitated solid was removed by vacuum filtration and the filtrate was collected. The filtrate was concentrated under reduced pressure, separated and purified by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-10%) to obtain compound BB-27-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40 - 7.26 (m, 4H), 7.22 - 7.16 (m, 1H), 4.20 - 4.14 (m, 2H) , 4.10 - 4.01 (m, 2H), 3.82 (s, 2H), 2.70 - 2.61 (m, 2H), 2.17 (t, J = 7.2 Hz, 2H ), 1.56 - 1.48 (m, 2H), 1.36 (s, 6H), 1.29 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7. 2Hz, 3H)

Step 3: Synthesis of compound BB-27-4.

Compound BB-27-3 (8.5 g, 25.34 mmol) was dissolved in tetrahydrofuran (250 mL), sodium hydride (3.04 g, 76.02 mmol, 60% purity) was added and the mixture was was heated to 80° C. and stirred for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 100 mL of water was added, and the pH was adjusted to 5 with dilute hydrochloric acid while the temperature was kept below 10°C with an ice bath. Solid sodium bicarbonate was added to neutralize and extracted with ethyl acetate (250 mL x 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound BB-27-4. Used directly for next reaction without purification. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.41 (s, 1H), 7.40 - 7.29 (m, 5H), 4.23 - 4.18 (m, 2H), 3.61 (s, 2H), 2.51 (t, J = 5.6 Hz, 2H), 2.16 (t, J = 5.6 Hz, 2H), 1.39 (s, 6H), 1.28 (t, J=7.2Hz, 3H)

Step 4: Synthesis of compound BB-27-5.

Compound BB-27-4 (7.1 g, 24.54 mmol) was dissolved in 6M (177.50 mL) hydrochloric acid, heated to 110° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, solid sodium hydroxide was added to adjust the pH to 8, and extracted with ethyl acetate (250 mL×2). The organic phases were combined, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound BB-27-5. Used directly for next reaction without purification. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39 - 7.24 (m, 5H), 3.62 (s, 2H), 2.65 (t, J = 6.0 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 1.87 - 1.77 (m, 2H), 1.30 (s, 6H)

Step 5: Synthesis of compound BB-27-6.

Compound BB-27-5 (2.5 g, 11.50 mmol) was added to methanol (10 mL), wet palladium on carbon (100 mg, 10% purity) was added and the reaction was purged with hydrogen (30 PSI). Place in atmosphere and stir at 25° C. for 3 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound BB-27-6, which was directly used in the next reaction. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.08 - 2.99 (m, 2H), 2.49 (t, J = 6.8 Hz, 2H), 2.08 - 1.98 (m , 2H), 1.25(s, 6H)

Step 6: Synthesis of compound BB-27-7.

Compound BB-27-6 (1.25 g, 9.83 mmol) was dissolved in dichloromethane (35 mL) and treated with 35 mL aqueous sodium bicarbonate (2.48 g, 29.48 mmol) and fluorenylmethyl chloride. Oxycarbonyl (2.54 g, 9.83 mmol) was added respectively. The reaction was stirred at 25° C. for 2 hours. After completion of the reaction, dichloromethane (30 mL×2) was added for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, separated and purified by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-30%) to obtain compound BB-27-7.

Step 7: Synthesis of compound BB-27-8.

Compound BB-27-7 (497 mg, 1.42 mmol) was dissolved in methanol (10 mL), sodium borohydride (53.81 mg, 1.42 mmol) was added at 0 °C, and the reaction mixture was C. and stirred for 1 hour. After completion of the reaction, 10 mL of acetone was added to quench, and the reaction solution was concentrated under reduced pressure. 10 mL of water was added and extracted with dichloromethane (25 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, separated and purified by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-35%) to obtain compound BB-27-8.

Step 8: Synthesis of compound BB-27-9.

Compound BB-27-8 (790 mg, 2.25 mmol) was dissolved in dichloromethane (80 mL), triethylamine (568.66 mg, 5.62 mmol), 4-dimethylaminopyridine (274.63 mg, 2 .25 mmol) and p-toluenesulfonyl chloride (642.85 mg, 3.37 mmol) were added respectively and the reaction was stirred at 40° C. for 12 hours. After completion of the reaction, the reaction solution was directly concentrated to dryness, separated and purified by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-20%) to obtain compound BB-27-9.

Step 9: Synthesis of compound BB-27-10.

Compound BB-26 (285 mg, 1.00 mmol) was dissolved in methanol (15 mL), potassium carbonate (347.01 mg, 2.51 mmol) was added and the reaction was heated to 60° C. Stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, dissolved in dimethylformamide (35 mL), and treated with potassium carbonate (340.18 mg, 2.46 mmol) and compound BB-27-9 (497.81 mg, 984.54 μmol). ) were added respectively. The reaction solution was heated to 60° C. and stirred for 1 hour. After completion of the reaction, the reaction solution was poured into 150 mL of water to quench, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, separated and purified by high performance preparative chromatography (eluent: methanol/dichloromethane = 0-20%) to obtain compound BB-27-10.

Step 10: Synthesis of compound BB-27-11.

Compound BB-27-10 (20 mg, 56.67 μmol) was dissolved in dichloromethane (5 mL) and treated with 2 mL aqueous sodium bicarbonate (14.28 mg, 170.01 μmol) and fluorenylmethyloxycarbonyl chloride. (14.66 mg, 56.67 μmol) were added respectively. The reaction was stirred at 25° C. for 2 hours. After completion of the reaction, the reaction solution was poured into 10 mL of water and extracted by adding dichloromethane (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound BB-27-11, which was used directly in the next reaction.

Step 11: Synthesis of compound BB-27-12.

Compound BB-27-11 (35 mg, 60.85 μmol) was dissolved in dichloromethane (5 mL) and m-chloroperoxybenzoic acid (98.83 mg, 486.82 μmol, 85% purity) was added portionwise. and the reaction was stirred at 25° C. for 16 hours. After the reaction was completed, it was quenched by adding 2 mL of saturated sodium thiosulfate solution and 5 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound BB-27-12, which was used directly in the next reaction.

Step 12: Synthesis of compound BB-27.

Compound BB-27-12 (35 mg, 57.65 μmol) was dissolved in ethanol (5 mL), concentrated hydrochloric acid (12 M, 480.38 μL) was added, and the reaction was heated to 85° C. for 16 Stirred for hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, dissolved by adding 30 mL of ethyl acetate, washed with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), and diluted with anhydrous sodium sulfate. Dried and filtered. The filtrate was concentrated under reduced pressure to give compound BB-27, which was used directly in the next reaction.

Example 1: WX001, WX001A, WX001B

Synthetic route:

Step 1: Synthesis of compound WX001-1.

Compound BB-4 (3.25 g, 7.11 mmol) was dissolved in 15 mL of ethanol, concentrated hydrochloric acid (12 M, 9.5 mL) was added, heated to 80° C. and stirred overnight. After the reaction was completed, the solvent was removed under reduced pressure, the pH was adjusted to 12 with 2 M NaOH, and the crude product solution was directly used for the next reaction.

Step 2: Synthesis of compound WX001-2.

10 mL of ethyl acetate was added to the above crude product solution, Boc ₂ O (1.55 g, 7.12 mmol, 1.64 mL) was added and reacted at 0° C. for 1.5 hours. After completion of the reaction, 20 mL of ethyl acetate was added to dilute and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (15 mL×3), and dried over anhydrous sodium sulfate. Filtration and concentration gave the crude product, which was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-25%) to give the desired compound WX001-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.47 (br s, 1H), 6.92 - 6.86 (m, 1H), 6.81 (d, J = 8.2 Hz, 1H) , 4.26 (br s, 1H), 4.04 (br s, 3H), 3.76 - 3.66 (m, 1H), 3.08 (br s, 1H), 2.76 (br t , J = 12.6 Hz, 1H), 2.21 (br d, J = 10.4 Hz, 1H), 1.98 - 1.84 (m, 2H), 1.58 (s, 1H), 1.42 (s, 9H).

Step 3: Synthesis of compound WX001-3.

Triphosgene (158 mg, 532.43 μmol) was dissolved in 5 mL DCM and BB-5 (220 mg, 1.60 mmol) and triethylamine (54.36 mg, 537.25 μmol, 74.47 μL) were added. After addition, the mixture was stirred at room temperature for 30 minutes to react, and then the reaction solution was concentrated. The resulting crude product was dissolved in 5 mL of DCM, WX001-2 (200 mg, 511.67 μmol) and triethylamine (117.01 mg, 1.16 mmol, 160.29 μL) were added, and the Stir overnight. After completion of the reaction, the crude product WX001-3 obtained by concentrating the reaction solution was used directly in the next reaction.

Step 4: Synthesis of compound WX001.

Compound WX001-3 (300.00 mg, 541.47 μmol) was dissolved in 5 mL of ethyl acetate, HCl/EtOAc (4 M, 4.00 mL) was added and the reaction was stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the target compound WX001. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.57 - 1.75 (m, 2 H) 1.74 - 1.93 (m, 7 H) 1.96 (br d, J = 13. 2 Hz, 2 H) 2.89 (br s, 2 H) 3.11 (br t, J = 11.6 Hz, 1 H) 3.24 (br d, J = 12.0 Hz, 1 H) 3.42 - 3.46 (m, 1 H) 4.16 (br t, J = 11.4 Hz, 1 H) 4.63 - 4.71 (m, 1 H) 6.37 (s, 1 H) 7.17 (d, J = 9.0 Hz, 1 H) 7.36 - 7.49 (m, 2 H) 8.22 (d, J = 8.8 Hz, 1 H) 8.56 (s, 1 H) 8.82 - 9.59 (m, 2 H) 10.92 (br s, 1 H).

Step 5: Synthesis of compounds WX001A, WX001B.

Compound WX001 was subjected to supercritical fluid chromatography (separation conditions: column, Chiralpak AD-3 100×4.6 mm ID, 3 μm; mobile phase, A: carbon dioxide B: methanol (0.05% diethylamine) flow rate: 2.8 mL/min; column temperature: 40° C.; detection wavelength: 220 nm) to give the chiral isomers WX001A and WX001B, whose retention times are 4.883 min, 5 .875 minutes and the ratio is 1:1.

Example 2: WX002, WX002A, WX002B

Synthetic route:

Step 1: Synthesis of compound WX002-1.

Compound BB-6 (10.80 g, 34.20 mmol) was dissolved in 60 mL of ethanol, concentrated hydrochloric acid (12 M, 20 mL) was added, heated to 80° C. and stirred overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, adjusted to pH=7 with 1 M NaOH, and extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated brine (30 mL×3), and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-30%) to obtain the desired compound WX002-1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (d, J = 7.0 Hz, 6 H) 3.89 (spt, J = 6.8 Hz, 1 H) 6.78 - 6 .83 (m, 1 H) 6.85 - 6.91 (m, 1 H) 10.62 (s, 1 H).

Step 2: Synthesis of compound WX002.

BB-5 (219.74. mg, 1.60 mmol) was dissolved in 5 mL DCM and triphosgene (156.87 mg, 528.61 μmol) and triethylamine (81.05 mg, 800.93 μmol, 111 03 μL) was added, and the reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The resulting crude product was dissolved in 5 mL of DCM and WX002-1 (200 mg, 800.93 μmol) and triethylamine (162.09 mg, 1.60 mmol, 222.04 μL) were added and Stir overnight. After completion of the reaction, the reaction solution was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the target compound WX002.

Step 3: Synthesis of compounds WX002A, WX002B.

Compound WX002 was separated by supercritical fluid chromatography (separation conditions: column, Chiralpak AD (250 mm × 30 mm, 5 μm); mobile phase, A: carbon dioxide B: methanol (0.1% ammonia water)). chiral isomers WX002A and WX002B can be obtained with retention times of 4.803 min and 5.672 min, respectively, in a 1:1 ratio.

Each example in Table 1 can be synthesized using BB-1 in step 2 with reference to the synthesis method of steps 1-3 of example 2. The structures in the table also represent their possible isomers.

Example 4: WX004, WX004A, WX004B

Synthetic route:

Step 1: Synthesis of compound WX004.

BB-1 (105.28 mg, 767.50 μmol) was dissolved in 5 mL DCM and triphosgene (75.16 mg, 253.28 μmol) and triethylamine (77.66 mg, 767.50 μmol, 106. 83 μL) was added, and the mixture was stirred at room temperature for 30 minutes to react, and then the reaction solution was concentrated. The resulting crude product was dissolved in 5 mL of DCM, WX001-2 (150.00 mg, 383.75 μmol) and triethylamine (38.83 mg, 383.75 μmol, 53.41 μL) were added, Stir overnight at room temperature. After completion of the reaction, the reaction solution was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the desired compound WX004.

Step 2: Synthesis of compounds WX004A, WX004B.

Compound WX004 was subjected to supercritical fluid chromatography (separation conditions: column, ChiralCel OD-H 150×4.6 mm ID, 5 μm; mobile phase, A: carbon dioxide B: ethanol (0.05% diethylamine) flow rate: 2.5 mL/min; column temperature: 40° C.; detection wavelength: 220 nm) to give the chiral isomers WX004A and WX004B, whose retention times are 4.499 min, 5 .163 minutes and the ratio is 1:1.

Example 5: WX005, WX005A, WX005B

Synthetic route:

Step 1: Synthesis of compound WX005-1.

Compound BB-6 (1 g, 3.17 mmol) was dissolved in 30 mL of THF and LiHMDS (1 M, 6.33 mL) was added dropwise at -70°C. After stirring at −70° C. for 0.5 hours, iodomethane (3.7 g, 26.07 mmol, 1.62 mL) was added and the reaction continued for 3 hours. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, diluted with 25 mL of ethyl acetate, and then extracted with ethyl acetate (25 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-25%) to obtain the desired product. to obtain compound WX005-1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (dd, J = 1.1, 8.4 Hz, 1H), 7.36 - 7.31 (m, 1H), 1.35 (s , 9H), 1.29 (s, 9H).

Step 2: Synthesis of compound WX005-2.

Compound WX005-1 (0.447 g, 1.36 mmol) was dissolved in 10 mL of ethanol, concentrated hydrochloric acid (12 M, 2 mL) was added, heated to 80° C. and stirred overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, adjusted to pH=12 with 2 M NaOH, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-25%) to obtain the desired product. to obtain compound WX005-2 of ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.36 (s, 1H), 6.93 - 6.87 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 1.47 (s, 9H).

Step 3: Synthesis of compound WX005.

Compound BB-1 (208.05 mg, 1.52 mmol) was dissolved in 5 mL of DCM, triphosgene (148.52 mg, 500.49 μmol) and triethylamine (153.47 mg, 1.52 mmol, 211 0.10 μL) was added, and the reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The resulting crude product was dissolved in 5 mL of DCM and compound WX005-2 (200.00 mg, 758.32 μmol) and triethylamine (76.73 mg, 758.32 μmol, 105.55 μL) were added. was stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the desired compound WX005.

Step 4: Synthesis of WX005A, WX005B.

Compound WX005 was subjected to supercritical fluid chromatography (separation conditions: column, ChiralCel OD-H 150×4.6 mm ID, 5 μm; mobile phase, A: carbon dioxide B: ethanol (0.05% diethylamine) flow rate: 2.5 mL/min; column temperature: 40° C.; detection wavelength: 220 nm) to give the chiral isomers WX005A and WX005B, whose retention times are 4.205 min and 5 min, respectively. .142 minutes and the ratio is 1:1.

Example 6: WX006, WX006A, WX006B

Synthetic route:

Step 1: Synthesis of compound WX006-1.

The crude compound BB-2 (6.95 g, 28.75 mmol) was dissolved in 120 mL of DMF and treated with potassium carbonate (3.98 g, 28.80 mmol) and 1-bromo-3-chloropropane ( 5.44 g, 34.55 mmol) was added and the reaction was stirred at 80° C. for 16 hours to react. After completion of the reaction, the solvent was distilled off under reduced pressure, 100 mL of water was added to the resulting residue, and the mixture was extracted with ethyl acetate (80 mL x 3). The obtained organic phases were combined and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the crude product obtained by concentration was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-10%) to obtain the desired compound WX006-1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.53 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.72 (t, J = 6.2 Hz, 2H), 3.29 (t, J = 6.8 Hz, 2H), 2.13 - 1.93 (m, 2H), 1.53 (s, 9H).

Step 2: Synthesis of compound WX006-2.

Compound WX006-1 (3.28 g, 10.31 mmol) was dissolved in 100 mL of DCM, m-CPBA (12.55 g, 61.84 mmol) was added at -10 °C, and 5 The mixture was stirred for hours to react. After the reaction was complete, 50 mL of saturated sodium sulfite solution, 50 mL of saturated sodium bicarbonate solution and 50 mL of DCM were added. The aqueous phase was extracted with DCM (50 mL x 3) and the organic phases were combined and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the crude product obtained by concentration was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-15%) to obtain the desired compound WX006-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.85 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.74 - 3. 64 (m, 4H), 2.44 - 2.28 (m, 2H), 1.54 (s, 9H).

Step 3: Synthesis of compound WX006-3.

Compound WX006-2 (2.61 g, 7.45 mmol) was dissolved in 60 mL tetrahydrofuran, cooled to −70° C., then KHMDS (1.64 g, 8.20 mmol) was added, and the reaction mixture was The reaction was continued at -70°C for 1 hour while stirring. After completion of the reaction, 20 mL of water was added to quench, diluted with 30 mL of ethyl acetate, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). After the organic phases were combined, they were dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was separated on a chromatography column (developing solvent: ethyl acetate/petroleum ether = 0-15%) to obtain the desired compound WX006-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 3.09 (tt, J = 4.6, 8.0 Hz, 1H), 1.53 (s, 9H), 1.51 - 1.48 (m, 2H), 1.15 - 1.09 (m, 2H).

Step 4: Synthesis of compound WX006-4.

Compound WX006-3 (2.05 g, 6.53 mmol) was dissolved in 40 mL of ethanol, concentrated hydrochloric acid (12 M, 9 mL) was added, heated to 80° C. and stirred overnight. After completion of the reaction, the solvent was removed under reduced pressure, saturated sodium bicarbonate solution was added to the resulting residue to adjust pH=9, and the aqueous phase was extracted with ethyl acetate (50 mL×3). After the organic phases were combined, they were dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was separated on a chromatography column (developing solvent: ethyl acetate/petroleum ether = 0-25%) to obtain the desired compound WX006-4. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 6.90 - 6.86 (m, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.09 - 3.93 (m, 2H), 3.22 (tt, J = 4.6, 8.0 Hz, 1H), 1.46 - 1.39 (m, 2H), 1.18 - 1.10 (m, 2H).

Step 5: Synthesis of compound WX006.

Compound BB-1 (0.84 g, 6.12 mmol) was dissolved in 20 mL of DCM and triphosgene (0.55 g, 1.85 mmol) and triethylamine (620.95 mg, 6.14 mmol) were added. After addition, the mixture was stirred at room temperature for 30 minutes to react, and then the reaction solution was concentrated. The resulting crude product was dissolved in 20 mL of DCM and compound WX006-4 (0.76 g, 3.07 mmol) and triethylamine (310.48 g, 3.07 mmol) were added and stirred overnight at room temperature. Stirred. After completion of the reaction, the reaction mixture was concentrated, and the resulting crude product was separated by high-performance liquid chromatography and further separated by a chromatography column (eluent: ethyl acetate/petroleum ether = 0-40%), The desired compound WX006 was obtained.

Step 6: Synthesis of compounds WX006A, WX006B.

Compound WX006 was subjected to supercritical fluid chromatography (separation conditions: column, Chiralpak AD-3 150×4.6 mm ID, 3 μm; mobile phase, A: carbon dioxide B: methanol (0.05% diethylamine); column temperature: 40° C.; detection wavelength: 220 nm) to give chiral isomers WX006A and WX006B with retention times of 6.531 min and 7.531 min, respectively. 085 minutes and the ratio is 1:1.

Example 7: WX007, WX007A, WX007B

Synthetic route:

Step 1: Synthesis of compound WX007-1.

Compound BB-2 (1.5 g, 6.21 mmol) was dissolved in 30 mL of DMF, potassium carbonate (1 g, 7.24 mmol) and bromoethane (730 mg, 6.70 mmol, 0.5 mL). ) was added and stirred overnight at 80°C. After completion of the reaction, the solvent was distilled off under reduced pressure, 50 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL×2) and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-5%) to give compound WX007-1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 3.20 (q, J = 7.4 Hz, 2H), 1.53 (s, 9H), 1.33 - 1.29 (m, 3H).

Step 2: Synthesis of compound WX007-2.

Compound WX007-1 (0.84 g, 3.11 mmol) was dissolved in 20 mL of DCM, m-CPBA (3.79 g, 18.68 mmol) was added at °C and stirred at -10 °C for 5 hours. and reacted. After the reaction was complete, 40 mL of saturated sodium sulfite solution, 40 mL of saturated sodium bicarbonate solution and 30 mL of DCM were added. The solution was extracted with DCM (30 mL x 3) and the resulting organic phases were combined and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the filtrate is evaporated under reduced pressure and the crude product is separated by chromatography column (eluent: ethyl acetate/petroleum ether = 0-25%) to give the desired compound WX007. -2 was obtained. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 3.50 (q, J = 7.4 Hz, 2H), 1.53 (s, 9H), 1.37 (t, J = 7.4 Hz, 3H).

Step 3: Synthesis of compound WX007-3.

Compound WX007-2 (0.82 g, 2.72 mmol) was dissolved in 10 mL of ethanol, concentrated hydrochloric acid (12 M, 3 mL) was added, heated to 80° C. and stirred overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, saturated sodium bicarbonate solution was added to adjust pH=9, and extracted with ethyl acetate (30 mL×3). After combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentration, the crude product obtained is separated on a chromatographic column (eluent: ethyl acetate/petroleum ether = 0-35%). , to obtain the desired compound WX007-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.60 (s, 1H), 6.89 - 6.84 (m, 1H), 6.84 - 6.79 (m, 1H), 3.54 (q, J=7.4 Hz, 2H), 1.36 (t, J=7.4 Hz, 3H).

Step 4: Synthesis of compound WX007.

Compound BB-1 (93.13 mg, 678.86 μmol) was dissolved in 5 mL DCM and treated with triphosgene (60.44 mg, 203.66 μmol) and triethylamine (68.69 mg, 678.86 μmol, 94 0.49 μL) was added and the reaction was stirred at room temperature for 30 minutes, after which the reaction was concentrated. The resulting crude product was dissolved in 5 mL DCM and compound WX007-3 (0.08 g, 339.43 μmol) and triethylamine (34.35 mg, 339.43 μmol, 47.24 μL) were added. was stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the target compound WX007.

Step 5: Synthesis of compounds WX007A, WX007B.

Compound WX007 was separated by supercritical fluid chromatography (separation conditions: column, column, AD (250 mm × 30 mm, 5 μm); mobile phase, isopropanol (0.1% aqueous ammonia) to give chiral isomers WX007A and WX007B. with retention times of 5.048 min and 5.605 min, respectively, with a ratio of 1:1.

Each example in Table 2 was synthesized using a different fragment in step 1, referring to the synthetic method of steps 1-5 of example 7. The structures in the table also represent their possible isomers.

Example 13: WX013, WX013A, WX013B

Synthetic route:

Step 1: Synthesis of compound WX013-1.

Compound BB-4 (0.58 g, 1.27 mmol) was dissolved in 10 mL of ethanol, concentrated hydrochloric acid (12 M, 1.5 mL) was added, heated to 80° C. and stirred overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, adjusted to pH=9 with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL×3). After combining the organic phases, drying over anhydrous sodium sulphate, filtering and concentrating, the crude product obtained is separated on a chromatography column (eluent: methanol/dichloromethane=0-5%) to give the compound WX013-1 was obtained. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 6.92 - 6.85 (m, 2H), 4.60 (br s, 2H), 3.89 - 3.79 (m, 1H), 3 .27 (br s, 1H), 3.01 (br d, J=11.8 Hz, 1H), 2.91 (dd, J=10.6, 12.4 Hz, 1H), 2.65 - 2.55 (m, 1H), 2.11 - 2.03 (m, 1H), 1.90 - 1.80 (m, 2H), 1.55 (br d, J = 14.6 Hz, 1H ).

Step 2: Synthesis of compound WX013-2.

Compound WX013-1 (0.2 g, 687.84 μmol) was dissolved in 3 mL water and treated with triethylamine (174.48 mg, 1.72 mmol, 240 μL) and N-[2-(trimethylsilyl)ethoxycarbonyl Oxy]succinimide (0.17 g, 655.53 μmol) in dioxane solution (3 mL) was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, diluted with 10 mL of water, and extracted with ethyl acetate (10 mL x 3). After combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentration, the crude product obtained is separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-30%). , to obtain the desired compound WX013-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.41 (s, 1H), 6.86 - 6.81 (m, 1H), 6.81 - 6.76 (m, 1H), 4.36 (br d, J = 12.4 Hz, 1H), 4.10 - 4.06 (m, 1H), 4.00 (br s, 2H), 3.73 - 3.63 (m, 1H), 3.09 (br s, 1H), 2.81 - 2.71 (m, 1H), 2.13 (br d, J = 12.8 Hz, 1H), 1.93 - 1.79 (m, 2H), 1.51 - 1.43 (m, 1H), 0.94 (t, J = 8.4 Hz, 2H), 0.00 (s, 9H).

Step 3: Synthesis of compound WX013-3.

Compound BB-5 (0.35 g, 2.55 mmol) was dissolved in 10 mL of DCM and triphosgene (0.23 g, 775.07 μmol) and triethylamine (259.13 mg, 2.56 mmol, 356 0.44 μL) was added and the reaction was stirred at room temperature for 30 minutes, after which the reaction was concentrated. The resulting crude product was dissolved in 10 mL of DCM and compound WX013-2 (0.557 g, 1.28 mmol) and triethylamine (129.57 mg, 1.28 mmol, 178.22 μL) were added. was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated, and the obtained crude product WX013-3 was used directly in the next reaction.

Step 4: Synthesis of compound WX013.

Compound WX013-3 (0.765 g, 1.28 mmol) was dissolved in 15 mL of THF, replaced with nitrogen three times, TBAF (1 M, 5 mL) was added, and the reaction was stirred at 50° C. for 48 hours. let me After completion of the reaction, the solvent was distilled off under reduced pressure, diluted with 20 mL of water, and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product which was separated by high performance liquid chromatography to obtain compound WX013.

Step 5: Synthesis of compounds WX013A, WX013B.

Compound WX013 is separated by supercritical fluid chromatography (separation conditions: column, AD (250 mm×30 mm, 10 μm); mobile phase, ethanol (0.1% aqueous ammonia) to give chiral isomers WX013A and WX013B. with retention times of 3.126 min and 5.932 min, respectively, with a ratio of 1:1.

Example 14: WX014

Synthetic route:

Step 1: Synthesis of compound WX014-1.

The crude compound BB-2 (5 g, 20.68 mmol) and potassium carbonate (2.86 g, 20.68 mmol) were dissolved in 100 mL of DMF, followed by N-(2-bromoethyl)phthalimide ( 5.25 g, 20.68 mmol) was added and stirred at 80° C. for 18 hours to react. After completion of the reaction, the solvent was distilled off under reduced pressure, 50 mL of water and 50 mL of ethyl acetate were added to the resulting residue, and the mixture was extracted with ethyl acetate (40 mL x 3). The obtained organic phases were combined, washed successively with water (20 mL×3) and 30 mL of saturated brine, and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was distilled off from the filtrate under reduced pressure, and the resulting crude product was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-20%) to obtain the desired product. to obtain compound WX014-1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9 H) 3.47 (t, J = 6.6 Hz, 2 H) 3.85 (t, J = 6.6 Hz, 2 H) 7.13 (d, J = 8.4 Hz, 1 H) 7.27 (d, J = 8.4 Hz, 1 H) 7.57 - 7.62 (m, 2 H) 7. 63-7.68 (m, 2H).

Step 2: Synthesis of compound WX014-2.

Compound WX014-1 (2 g, 4.82 mmol) was dissolved in 50 mL of DCM, m-CPBA (5.87 g, 28.92 mmol) was added portionwise at -10 °C, and the temperature was adjusted from -10 °C to 20 °C. ℃ for 20 hours to react. After the reaction was completed, 40 mL of saturated sodium sulfite solution, 40 mL of saturated sodium bicarbonate solution and 50 mL of ethyl acetate were added. It was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 2), and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the filtrate was distilled under reduced pressure to remove the solvent and slurried with a mixed solvent (PE:EA=20:1) to obtain the intended compound WX014-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57 (s, 9 H) 4.00 - 4.12 (m, 2 H) 4.17 (t, J = 6.2 Hz, 2 H ) 7.26 (s, 1 H) 7.59 (d, J = 8.6 Hz, 1 H) 7.70 (s, 4 H).

Step 3: Synthesis of compound WX014-3.

Compound WX014-2 (2 g, 4.48 mmol) was dissolved in 10 mL of ethanol, concentrated hydrochloric acid (12 M, 10 mL) was added, heated to 80° C. and stirred overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, saturated sodium bicarbonate solution was added to the resulting residue to adjust pH=7, and extracted with ethyl acetate (20 mL×3). The obtained organic phases were combined, washed with 10 mL of saturated brine, and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 20/1 to 2/1) to obtain the desired compound WX014-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.05 - 4.09 (m, 2 H) 4.11 (br d, J = 6.8 Hz, 2 H) 4.15 (d, J = 7.2 Hz, 2 H) 6.58 (d, J = 8.4 Hz, 1 H) 6.66 - 6.72 (m, 1 H) 7.75 - 7.78 (m, 2 H) 7.80 - 7.84 (m, 2 H) 10.40 (s, 1 H).

Step 4: Synthesis of compound WX014.

Compound BB-1 (111.31 mg, 811.44 μmol) was dissolved in 5 mL of DCM, triphosgene (79.49 mg, 267.86 μmol) and triethylamine (159.44 mg, 1.58 mmol, 219 0.31 μL) was added, and the reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The resulting crude product was dissolved in 5 mL of DCM and compound WX014-3 (0.3 g, 787.81 μmol) and triethylamine (79.72 mg, 787.81 μmol, 109.65 μL) were added. and stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the desired compound WX014. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.54 (br s, 1H), 8.03 (br s, 1H), 7.89 (br s, 1H), 7.74 (br d, J = 9.2 Hz, 4H), 7.57 (br s, 1H), 7.41 (br d, J = 7.0 Hz, 1H), 6.86 (br s, 1H), 6.35 (br s, 1H), 4.80 (br s, 1H), 4.20 (br s, 2H), 4.02 (br s, 2H), 3.17 (br s, 1H), 2.39 (br s, 1H), 1.94 (br s, 1H), 1.76 (br s, 3H).

Example 15: WX015

Synthetic route:

Step 1: Synthesis of compound WX015.

Compound WX014 (0.428 g, 786.80 μmol) was added to 5 mL of ethanol, hydrazine hydrate (2.06 g, 34.98 mmol, 2 mL) was added, and stirred at 80° C. for 30 minutes. reacted. After completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain the desired product WX015. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.64 − 1.82 (m, 4 H) 1.88 (br s, 1 H) 2.41 (br s, 1 H) 3.08 ( br s, 2 H) 3.64 (br t, J = 5.8 Hz, 2 H) 4.81 (br s, 1 H) 6.08 (d, J = 8.4 Hz, 1 H) 6 .30 (s, 1 H) 7.37 (br d, J = 8.4 Hz, 1 H) 7.50 (s, 1 H) 7.78 (d, J = 8.4 Hz, 1 H) 8.17 (s, 1 H).

Example 16: WX016, WX016A, WX016B

Synthetic route:

Step 1: Synthesis of compound WX016.

Compound WX015 (0.080 g, 193.30 μmol) and cyclopropanecarboxylic acid chloride (60.62 mg, 579.89 μmol, 52.71 μL) were added to 5 mL DCM and triethylamine (58.68 mg, 579.89 μmol, 80.71 μL) was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was separated by high performance liquid chromatography to obtain the product WX016.

Step 2: Synthesis of compounds WX016A, WX016B.

Compound WX016 was subjected to supercritical fluid chromatography (separation conditions: column, ChiralPak AD-3 150×4.6 mm ID, 3 μm; mobile phase, A: carbon dioxide B: ethanol (0.05% diethylamine); flow rate: 2.5 mL/min; column temperature: 40° C.; detection wavelength: 220 nm) to give the chiral isomers WX006A and WX006B, whose retention times are 7.007 min and 7.00 min, respectively. 668 minutes and the ratio is 1:1.

Example 17: WX017, WX017A, WX017B

Synthetic route:

Step 1: Synthesis of compound WX0017.

Compound WX015 (0.04 g, 96.65 μmol) and methyl chloroformate (1.3 g, 13.76 mmol, 1.07 mL) were added to 2 mL DCM and triethylamine (29.34 mg, 289. 94 μmol, 40.36 μL) was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain product WX017.

Step 2: Synthesis of compounds WX017A, WX017B.

Compound WX017 was subjected to supercritical fluid chromatography (separation conditions: column, ChiralPak AS-3 150 × 4.6 mm ID, 3 μm mobile phase, A: carbon dioxide B: ethanol (0.05% diethylamine); column temperature: 40° C.; detection wavelength: 220 nm) to give the chiral isomers WX017A and WX017B, whose retention times are 4.776 min and 5.215 min, respectively. minutes and the ratio is 1:1.

Example 18: WX018, WX018A, WX018B

Synthetic route:

Step 1: Synthesis of compound WX018-2.

Compound WX018-1 (1.26 g, 12.72 mmol, 1 mL) was dissolved in 20 mL DCM, triethylamine (1.45 g, 14.37 mmol, 2 mL) and chloroacetyl chloride (2.13 g, 18.86 mmol, 1.5 mL) was added and stirred at 0° C. for 2 hours to react. After the reaction was completed, it was quenched by adding 50 mL of water, diluted with 50 mL of DCM, and extracted with DCM (50 mL x 3). The organic phases were combined, then dried over anhydrous sodium sulfate, filtered and concentrated to give compound WX018-2. ¹ H NMR (400MHz, CHLOROFORM-d) δ ppm 6.83 (br s, 1H), 4.10 - 4.00 (m, 2H), 3.96 - 3.84 (m, 2H).

Step 2: Synthesis of compound WX018-3.

Compound BB-2 (2.47 g, 10.22 mmol) was dissolved in 50 mL DMF, potassium carbonate (1.5 g, 10.85 mmol), potassium iodide (1 g, 6.02 mmol). and WX018-2 (1.84 g, 10.49 mmol) were added and stirred at 80° C. for 2 hours to react. After completion of the reaction, the solvent was distilled off under reduced pressure, 50 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. Filtered and concentrated, the resulting crude product was separated by chromatography column (eluent: ethyl acetate/petroleum ether=0-20%) to give compound WX018-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.30 (br s , 1H), 3.94 (s, 2H), 3.86 (dq, J = 6.8, 9.0 Hz, 2H), 1.52 (s, 9H).

Step 3: Synthesis of compound WX018-4.

Compound WX018-3 (0.788 g, 2.07 mmol) was dissolved in 20 mL of DCM, m-CPBA (2.52 g, 12.42 mmol) was added portionwise at °C, and the mixture was stirred at -10 °C for 5 minutes. The mixture was stirred for hours to react. After the reaction was complete, 20 mL of saturated sodium sulfite solution, 20 mL of saturated sodium bicarbonate solution and 20 mL of DCM were added. Extracted with DCM (20 mL x 3) and the resulting organic phases were combined and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was separated by chromatography column (eluent: ethyl acetate/petroleum ether=0-30%) to give compound WX018-4. got ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.11 (br s , 1H), 4.51 (s, 2H), 3.92 - 3.83 (m, 2H), 1.54 (s, 9H).

Step 4: Synthesis of compound WX018-5.

Compound WX018-4 (0.61 g, 1.48 mmol) was dissolved in 10 mL of ethanol, concentrated hydrochloric acid (12 M, 5 mL) was added, heated to 80° C. and stirred overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, 30 mL of saturated sodium bicarbonate solution was added, and extracted with ethyl acetate (15 mL x 2). After combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentration, the crude product obtained is separated on a chromatography column (eluent: ethyl acetate/petroleum ether=0-50%). , to give compound WX018-5. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.29 (s, 1H), 6.92 - 6.87 (m, 1H), 6.85 - 6.81 (m, 1H), 4.51 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H).

Step 5: Synthesis of compound WX018-6.

Triphosgene (235.40 mg, 793.26 μmol) was dissolved in 10 mL DCM and compound BB-1 (326.46 mg, 2.38 mmol) and triethylamine (240.81 mg, 2.38 mmol, 331 0.24 μL) was added and the reaction was stirred at room temperature for 30 minutes, after which the reaction solution was concentrated. The resulting crude product was dissolved in 10 mL of DCM and compound WX018-5 (0.233 g, 793.26 μmol) and triethylamine (80.27 mg, 793.26 μmol, 110.41 μL) were added. was stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated to obtain the crude product compound WX018-6, which was directly used in the next reaction.

Step 6: Synthesis of compound WX018-7.

Compound WX018-6 (0.362 g, 792.30 μmol) was dissolved in 5 mL THF, 5 mL ethanol and 1 mL water and LiOH.HO (166.24 mg, 3.96 mmol) was added. was stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and separated by adding 20 mL of water and 30 mL of ethyl acetate. The aqueous phase was adjusted to pH=2 with 2N hydrochloric acid and extracted with ethyl acetate (30 mL×3), the organic phases were combined then dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product and used directly in the next reaction.

Step 7: Synthesis of compound WX018.

Compound WX018-7 (0.27 g, 629.60 μmol) was dissolved in 5 mL DMF, 2,2,2-trifluoroethylamine (74.84 mg, 755.52 μmol, 59.40 μL), HATU (0.36 g, 946.80 μmol) and triethylamine (127.42 mg, 1.26 mmol, 175.27 μL) were added and stirred overnight at 40°C. After completion of the reaction, the solvent was distilled off under reduced pressure, 40 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL×2), and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product obtained was separated on a chromatography column (eluent: ethyl acetate/petroleum ether=0-50%) to obtain the desired compound WX018.

Step 8: Synthesis of compounds WX018A, WX018B.

Compound WX018 was separated by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AS-H (250 mm × 30 mm, 5 μm); mobile phase, ethanol (0.1% aqueous ammonia)) to give the chiral isomer WX018A. and WX018B can be obtained with retention times of 4.070 min and 4.755 min, respectively, with a ratio of 1:1.

Table 3. NMR and MS data for each example

Each example in Table 3 can be synthesized using BB-7 in step 3 with reference to the synthetic method of steps 3-4 of Example 1. The structures in the table also represent their possible isomers.

WX019 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.54 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.58 (br d, J=8. 4 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.20 - 7.15 (m, 2H), 7.14 - 7.08 (m, 2H), 4.91 - 4 .81 (m, 1H), 4.18 (br t, J = 11.6 Hz, 1H), 3.24 (br d, J = 12.4 Hz, 1H), 3.11 (br t, J = 12.0 Hz, 1H), 2.94 - 2.70 (m, 6H), 2.04 - 1.66 (m, 10H)

[M+H] ⁺ : 464.0

Each example in Table 4 can be synthesized using benzyl bromide in step 1 by referring to the synthetic method of steps 1-4 of Example 5. The structures in the table also represent their possible isomers.

Compound WX020 was separated by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AY 250 mm × 30 mm, 20 μm; mobile phase, A: carbon dioxide B: ethanol (0.1% ammonia water); gradient, B%: 50%-50%) to give the chiral isomers WX020A and WX020B with retention times of 2.214 min and 4.890 min, respectively, in a 1:1 ratio.

Analytical conditions: Column: Lux Cellulose-2 150×4.6 mm I.D., 3 μm; mobile phase, A: carbon dioxide B: ethanol (0.05% diethylamine); gradient, 40% of B; flow rate: 2 .5 mL/min; column temperature: 40°C; detection wavelength: 220 nm

WX020A ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.41 (br s, 1H), 8.43 (br d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.54 - 7.45 (m, 2H), 7.36 - 7.22 (m, 5H), 7.15 (br s, 1H), 6.32 (d, J = 1.6 Hz, 1H ), 4.82 (br d, J = 7.6 Hz, 1H), 3.06 (s, 2H), 2.47 - 2.41 (m, 1H), 2.37 (br d, J = 6.8 Hz, 1H), 1.91 (m, 1H), 1.79 - 1.67 (m, 3H), 1.22 (s, 6H)

[M+H] ⁺ : 503.1

WX020B ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.40 (br s, 1H), 8.44 (br d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.54 - 7.44 (m, 2H), 7.36 - 7.23 (m, 5H), 7.17 (br d, J = 8.8 Hz, 1H), 6.32 (d, J = 1.6 Hz, 1H), 4.88 - 4.78 (m, 1H), 3.06 (s, 2H), 2.43 (br s, 1H), 2.39 - 2.30 (m , 1H), 1.98 - 1.87 (m, 1H), 1.79 - 1.66 (m, 3H), 1.22 (s, 6H)

[M+H] ⁺ : 503.1

Example 21: WX021, WX021A, WX021B

Synthetic route:

Step 1: Synthesis of compound WX021-1.

BB-8 is used in step 1 to synthesize the target compound WX021-1 by referring to the synthesis method of steps 1 and 2 of BB-4. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 4.26 - 4. 18 (m, 1H), 4.03 (s, 2H), 3.94 (s, 2H), 2.82 (m, 2H), 2.51 (m, 2H), 1.55 (s, 9H) ), 1.45 (s, 9H)

Step 2: Synthesis of compound WX021-2.

Compound WX021-1 (0.29 g, 0.62 mmol) was dissolved in 5 mL of ethanol and 5 mL of hydrochloric acid (12 M) was added. The reaction solution was stirred at 85° C. for 14 hours and then concentrated under reduced pressure. Redissolve in 5 mL of dichloromethane and add 5 mL of saturated aqueous sodium bicarbonate and fluorenylmethyloxycarbonyl chloride (0.141 g, 0.55 mmol). The reaction was stirred at 0°C for 15 minutes. After completion of the reaction, 10 mL of dichloromethane was added to dilute, liquid separation was performed, and the organic phase was retained. The aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (15 mL×2), and dried over anhydrous sodium sulfate. The crude product obtained after filtration and concentration was separated on a chromatography column (eluent: ethyl acetate/petroleum ether = 0-40%) to give compound WX021-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.47 (s, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.6 Hz, 2H), 7.36 - 7.30 (m, 2H), 7.28 - 7.22 (m, 2H), 6.81 - 6.76 (m, 1H), 6.75 - 6.70 ( m, 1H), 4.35 - 4.25 (m, 3H), 4.16 - 4.10 (m, 1H), 3.99 (s, 2H), 3.94 (s, 2H), 2 .68 (m, 2H), 2.53 - 2.41 (m, 2H)

Step 3: Synthesis of compound WX021-3.

Triphosgene (93.83 mg, 316.18 μmol) was dissolved in 5 mL of dichloromethane and compound BB-1 (130.12 mg, 948.54 μmol) and triethylamine (72.70 mg, 718.45 μmol, 0 .1 mL) was added, and the mixture was stirred at room temperature (18° C.) for 30 minutes to react, and then the reaction solution was concentrated. The resulting crude product was dissolved in 5 mL of dichloromethane, compound WX021-2 (166 mg, 316.18 μmol) and triethylamine (145.40 mg, 1.44 mmol, 0.2 mL) were added, and the mixture was stirred at room temperature. (18° C.) and stirred for 3.5 hours. After completion of the reaction, the reaction solution was directly concentrated and dried to obtain a crude product. The crude product WX021-3 was used directly in the next reaction.

Step 4: Synthesis of compound WX021.

Compound WX021-3 (0.2 g, 290.62 μmol) was dissolved in 10 mL of dichloromethane, diethylamine (7.10 g, 97.08 mmol) was added, and the reaction was stirred at 15° C. for 1 hour. After completion of the reaction, the reaction solution was directly concentrated and dried to obtain a crude product. The crude product was separated by high performance liquid chromatography to give the desired compound WX021.

Step 5: Synthesis of compounds WX021A, WX021B.

Compound WX021 was subjected to supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK IC 250 mm × 30 mm, 10 μm; mobile phase, A: carbon dioxide, B: isopropanol (0.1% aqueous ammonia); gradient, B%: 50 %-50%) to give the chiral isomers WX021A and WX021B, whose retention times are 7.251 min and 10.541 min, respectively, and the ratio is 1:1.

Analytical conditions: Column: ChiralPak IC-3 150×4.6 mm I.D., 3 um; mobile phase, A: carbon dioxide B: isopropanol (0.1% ethanolamine); gradient, B %: 40%; : 2.5 mL/min; column temperature: 40°C; detection wavelength: 220 nm

WX021A ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (br s, 1H), 8.18 (s, 1H), 7.72 (br s, 1H), 7.49 (d, J = 1.6 Hz, 1 H), 7.36 (br d, J = 8.4 Hz, 1 H), 6.30 (d, J = 1.6 Hz, 1 H), 6.05 (br s, 1 H) , 4.80 (br d, J = 4.1 Hz, 1H), 4.75 - 4.61 (m, 1H), 3.93 (br d, J = 6.4 Hz, 4H), 2. 44 (br d, J = 5.6 Hz, 2H), 1.93 - 1.84 (m, 1H), 1.80 - 1.66 (m, 3H), 1.51 (br s, 2H) , 0.87 - 0.83 (m, 2H)

[M+H] ⁺ : 466.0

WX021B ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (br s, 1H), 8.18 (s, 1H), 7.75 (br s, 1H), 7.50 (d, J = 1.6 Hz, 1 H), 7.37 (br d, J = 8.0 Hz, 1 H), 6.30 (d, J = 1.6 Hz, 1 H), 4.81 (br s, 1 H) , 4.73 - 4.63 (m, 1H), 3.97 - 3.90 (m, 4H), 2.44 (br s, 2H), 1.89 (br d, J = 4.8 Hz , 1H), 1.77 - 1.67 (m, 3H), 1.51 (br s, 2H), 0.87 - 0.84 (m, 2H)

[M+H] ⁺ : 466.0

Each example in Table 5 can be synthesized using a different fragment in step 1 by referring to the synthetic method of steps 1-4 of example 21. The structures in the table also represent their possible isomers.

Compound WX022 was separated by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AD 250 mm × 30 mm, 10 μm; mobile phase, A: carbon dioxide, B: isopropanol (0.1% aqueous ammonia); gradient, B %: 40%-40%), chiral isomers WX022A and WX022B can be obtained with retention times of 6.755 min and 8.006 min, respectively, with a ratio of 1:1.

Analytical conditions: Column: ChiralPak AD-3 150×4.6 mm I.D., 3 um; mobile phase, A: carbon dioxide B: isopropanol (0.1% ethanolamine); gradient, mobile phase B to 5.5 Adjust from 5% to 40% in minutes, hold 40% for 3 minutes, hold 5% for 1.5 minutes, flow rate: 2.5 mL / min; column temperature: 40 ° C.; detection wavelength: 220 nm

WX022A ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 7.94 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 6.52 (br d, J = 7.6 Hz, 1H), 6.26 (d, J = 1.6 Hz, 1H), 4.81 - 4.69 (m, 1H), 4.63 (s, 1H), 3.13 - 3.02 (m, 4H), 2.57 - 2.49 (m, 1H), 2.47 - 2.40 (m, 1H), 2.39 - 2.30 (m, 2H ), 2.13 (br t, J = 10.0 Hz, 2H), 2.01 (br s, 1H), 1.93 - 1.89 (m, 1H), 1.84 - 1.77 ( m, 2H), 1.37 - 1.33 (m, 3H), 1.12 (br s, 1H)

[M+H] ⁺ : 494.0

WX022B ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 7.94 (br d, J=8.8 Hz, 1H), 7.37 (s, 1H), 6.53 (br s, 1H), 6 .26 (s, 1H), 4.75 (s, 1H), 3.06 (br s, 4H), 2.51 (s, 1H), 2.44 (br d, J = 7.6 Hz, 1H), 2.35 (br s, 2H), 2.12 (br s, 2H), 2.01 (br s, 1H), 1.94 - 1.90 (m, 1H), 1.84 - 1.77 (m, 2H), 1.39 - 1.35 (m, 2H), 1.14 (br s, 2H)

[M+H] ⁺ : 494.0

Compound WX023 was separated by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AS-H 250 mm × 30 mm, 5 μm; mobile phase, A: carbon dioxide B: isopropanol (0.1% aqueous ammonia); gradient, B%: 50%-50%), to give chiral isomers WX023A and WX023B with retention times of 2.129 min and 3.461 min, respectively, in a 1:1 ratio.

Analytical conditions: Column: ChiralPak AS-3 150 x 4.6 mm I.D., 3 um; mobile phase, A: carbon dioxide B: isopropanol (0.05% diethylamine); , flow rate: 2.5 mL / min; column temperature: 40 ° C.; detection wavelength: 220 nm

WX023A ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.40 (br s, 1H), 8.13 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7 .51 - 7.47 (m, 1H), 7.37 (br d, J = 8.4 Hz, 1H), 6.30 (d, J = 1.6 Hz, 1H), 5.99 (d , J = 8.4 Hz, 1H), 4.81 (br d, J = 4.4 Hz, 1H), 4.35 (br s, 1H), 2.84 (br t, J = 10.8 Hz, 2H), 2.47 - 2.29 (m, 3H), 1.96 - 1.66 (m, 9H).

[M+H] ⁺ : 453.9

WX023B ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.50 (br s, 1H), 8.14 (s, 1H), 7.78 (br d, J = 8.4 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 1.6 Hz, 1H), 6. 09 (br s, 1H), 4.82 (br s, 1H), 4.33 (br s, 1H), 2.92 - 2.82 (m, 2H), 2.46 - 2.38 (m , 1H), 2.48 - 2.29 (m, 2H), 2.00 - 1.62 (m, 9H).

[M+H] ⁺ : 453.9

Example 24: WX024, WX024A, WX024B

Synthetic route:

Step 1: Synthesis of compound WX024-1.

The desired compound WX024-1 was synthesized by referring to the synthesis method of Step 2 of Example 21.

Step 2: Synthesis of compound WX024-2.

The target compound WX024-2 was synthesized using BB-11 by referring to the synthesis method of Step 5 of Example 6.

Step 3: Synthesis of compound WX024.

The target compound WX024 was synthesized by referring to the synthetic method of Step 4 of Example 21.

Step 4: Synthesis of compounds WX024A, WX024B.

Compound WX024 was separated by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALCEL OD-H 250 mm × 30 mm, 5 μm; mobile phase, A: carbon dioxide B: ethanol (0.1% aqueous ammonia); gradient, B%: 45%-45%), chiral isomers WX024A and WX024B were obtained with retention times of 4.376 min and 4.794 min, respectively, in a 1:1 ratio.

Analytical conditions: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um; mobile phase, A: carbon dioxide B: ethanol (0.1% ethanolamine); gradient, mobile phase B to 4.5 Adjust from 5% to 40% in minutes, hold 40% for 2.5 minutes, hold 5% for 1 minute, flow rate: 2.8 mL / min; column temperature: 40 ° C.; detection wavelength: 220 nm

WX024A ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.88 - 7.75 (m, 2H), 7.39 (br d, J = 8.4 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 6.85 (d, J = 5.2 Hz, 1H), 6.16 (br d, J = 8.4 Hz, 1H), 4.75 (br s, 1H ), 4.48 (br s, 1H), 3.12 - 2.98 (m, 2H), 2.78 (br d, J = 13.2 Hz, 2H), 2.74 - 2.66 ( m, 2H), 1.88 (br s, 2H), 1.78 (br s, 4H), 1.73 - 1.67 (m, 1H), 1.64 - 1.55 (m, 1H)

[M+H] ⁺ : 470.0

WX024B ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (br s, 1H), 7.82 - 7.72 (m, 1H), 7.41 - 7.28 (m, 1H), 7 .22 (br d, J = 5.2 Hz, 1 H), 6.86 (br d, J = 5.2 Hz, 1 H), 6.07 (br d, J = 8.0 Hz, 1 H), 4.75 (br s, 1H), 4.40 (br s, 1H), 3.08 - 2.86 (m, 2H), 2.69 (br d, J = 11.2 Hz, 4H), 1.90 (br d, J = 8.4 Hz, 2H), 1.84 - 1.71 (m, 4H), 1.63 (br s, 2H)

[M+H] ⁺ : 470.0

Each example in Table 6 can be synthesized using a different fragment in step 5 by referring to the synthesis method of steps 5-6 of example 6. The structures in the table also represent their possible isomers.

Compound WX025 was separated by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALCEL OJ-H 250 mm × 30 mm, 5 μm; mobile phase, A: carbon dioxide B: ethanol (0.1% aqueous ammonia); gradient, B %: 40%-40%), chiral isomers WX025A and WX025B were obtained with retention times of 3.994 min and 4.753 min, respectively, in a 1:1 ratio.

Analytical conditions: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um; mobile phase, A: carbon dioxide B: ethanol (0.05% diethylamine); gradient, mobile phase B over 4.5 min. After adjusting from 5% to 40%, holding 40% for 2.5 minutes, holding 5% for 1 minute, flow rate: 2.8 mL / min; column temperature: 40 ° C.; detection wavelength: 220 nm

WX025A ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.26 - 8.17 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 5.2 Hz, 1H), 6.90 (d, J = 5.2 Hz, 2H), 4.82 - 4.74 (m, 1H), 3.47 (br s, 1H), 2.84 - 2.64 (m, 2H), 1.98 - 1.78 (m, 3H), 1.73 - 1.62 (m, 1H), 1.18 (br d, J = 3.6 Hz, 2H), 1.15-1.05 (m, 2H)

[M+H] ⁺ : 427.0

WX025B ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.28 - 8.16 (m, 2H), 7.40 (br d, J = 8.0 Hz, 1H), 7.27 (d, J = 5.4 Hz, 1H), 6.90 (d, J = 5.2 Hz, 2H), 4.78 (br d, J = 5.6 Hz, 1H), 3.46 (br d, J = 4.4 Hz, 1H), 2.85 - 2.61 (m, 2H), 1.98 - 1.76 (m, 3H), 1.75 - 1.61 (m, 1H), 1. 21-1.07 (m, 4H)

[M+H] ⁺ : 427.0

Compound WX026 was separated by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALCEL OD 250 mm × 30 mm, 10 μm; mobile phase, A: carbon dioxide B: methanol (0.1% aqueous ammonia); B %: 35%-35%) to give the chiral isomers WX026A and WX026B with retention times of 3.351 min and 4.422 min, respectively, and a ratio of 1:1.

Analytical conditions: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 um; mobile phase, A: carbon dioxide B: methanol (0.05% diethylamine); gradient, mobile phase B over 4.5 min. After adjusting from 5% to 40%, holding 40% for 2.5 minutes, holding 5% for 1 minute, flow rate: 2.8 mL / min; column temperature: 40 ° C.; detection wavelength: 220 nm

WX026A ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (d, J = 3.6 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.22 (s , 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.21 (m, 1H), 7.06 (br d, J = 8.8 Hz, 1H), 4.95 - 4.86 (m, 1H), 2.93 - 2.81 (m, 2H), 2.01 - 1.81 (m, 4H) , 1.78 - 1.69 (m, 1H), 1.22 (br d, J = 4.4 Hz, 2H), 1.16 (br d, J = 7.6 Hz, 2H)

[M+H] ⁺ : 422.0

WX026B ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (br d, J = 3.6 Hz, 1 H), 8.30 (br d, J = 8.8 Hz, 1 H), 8.22 (s, 1H), 7.65 (br d, J=7.6 Hz, 1H), 7.50 (br d, J=8.4 Hz, 1H), 7.21 (dd, J=4. 8, 7.6 Hz, 1H), 7.05 (br d, J = 8.8 Hz, 1H), 4.95 - 4.86 (m, 1H), 2.93 - 2.79 (m, 2H), 2.04 - 1.79 (m, 4H), 1.78 - 1.68 (m, 1H), 1.22 (br d, J = 4.0 Hz, 2H), 1.16 ( br d, J = 7.6 Hz, 2H)

[M+H] ⁺ : 422.0

Compound WX027 was separated by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALCEL OD-H 250 mm × 30 mm, 5 μm; mobile phase, A: carbon dioxide B: methanol (0.1% aqueous ammonia); gradient, B %: 40%-40%), chiral isomers WX027A and WX027B were obtained with retention times of 2.212 min and 3.034 min, respectively, in a 1:1 ratio.

Analytical conditions: Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um; mobile phase, A: carbon dioxide B: methanol (0.05% diethylamine); gradient, 40% mobile phase B; : 2.5 mL / min; column temperature: 35 ° C.; detection wavelength: 220 nm

WX027A ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.30 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 7.07 ( br d, J = 8.8 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 5.08 - 5.00 (m, 1H), 4.62 (s, 2H) , 3.37 - 3.32 (m, 1H), 2.74 - 2.56 (m, 2H), 2.17 - 2.06 (m, 1H), 1.98 - 1.79 (m, 3H), 1.36-1.30 (m, 2H), 1.18 (br d, J = 5.6 Hz, 2H)

[M+H] ⁺ : 427.0

WX027B ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.31 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 7.09 ( d, J = 8.8 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 5.08 - 5.00 (m, 1H), 4.62 (br s, 2H) , 3.35 - 3.32 (m, 1H), 2.73 - 2.57 (m, 2H), 2.11 (dt, J = 5.2, 9.3 Hz, 1H), 1.99 - 1.78 (m, 3H), 1.38 - 1.30 (m, 2H), 1.19 (m, 2H)

[M+H] ⁺ : 427.0

WX028 ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.86 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.07 (br d, J=8. 8 Hz, 1H), 5.11 (m, 1H), 4.61 (s, 3H), 2.87 - 2.78 (m, 2H), 2.23 - 1.79 (m, 5H), 1.32 (br s, 2H), 1.18 (br d, J = 5.6 Hz, 2H)

[M+H] ⁺ : 428.0

Example 29: WX029, WX029A, WX029B

Synthetic route:

Step 1: Synthesis of compound WX029-1.

Compound BB-18 (750 mg, 1.46 mmol) was dissolved in dichloromethane (60 mL), triethylamine (369.84 mg, 3.65 mmol) and compound intermediate BB-15 (1.62 g, 5. 12 mmol) were added respectively and the mixture was stirred at 40° C. for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane (100 mL) and washed with water (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product. Separation and purification by high performance preparative chromatography (eluent: ethyl acetate/petroleum ether = 0-30%) gave compound WX029-1.

Step 2: Synthesis of compound WX029.

Compound WX029-1 (40 mg, 57.95 μmol) was dissolved in dichloromethane (5 mL), diethylamine (355.00 mg, 4.85 mmol, 0.5 mL) was added, and the reaction was stirred at 25°C for 1 Stirred for hours. After completion of the reaction, the reaction solution was diluted with 20 mL of dichloromethane, washed with 20 mL of water and 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product got The crude product was separated by high performance liquid chromatography (neutral method) to give WX029. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 8.07 - 7.96 (m, 1H), 6.63 (br d, J = 8.4 Hz, 1H), 5.81 (s, 1H) , 4.15 (br s, 1H), 3.47 (m, 1H), 3.16 - 3.07 (m, 2H), 2.85 - 2.73 (m, 1H), 2.48 - 2.32 (m, 2H), 2.21 (s, 3H), 2.04 (m, 1H), 1.99 - 1.63 (m, 8H)

Step 3: Synthesis of compounds WX029A, WX029B.

Compound WX029 (58 mg, 123.94 μmol) was subjected to supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AD-H 250 mm × 30 mm, 5 μm; mobile phase, A: carbon dioxide B: ethanol (0.1% of aqueous ammonia); gradient, B%: 40%-40%) to give the chiral isomers WX029A and WX029B with retention times of 5.922 min and 7.134 min, respectively; The ratio is 1:1.

Example 30: WX030, WX030A, WX030B

Synthetic route:

Step 1: Synthesis of compound WX030-1.

Compound WX030-1 was synthesized from compound BB-17 by referring to the synthesis method of WX029-1 in Example 29.

Step 2: Synthesis of compound WX030.

Compound WX030 was synthesized from compound WX030-1 by referring to the method for synthesizing WX029 in Example 29. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 7.99 - 7.93 (m, 1H), 6.79 (s, 1H), 6.60 - 6.56 (m, 1H), 4.96 (s, 1H), 4.27 (br s, 1H), 3.58 - 3.54 (m, 1H), 3.16 - 3.08 (m, 2H), 2.82 - 2.79 ( m, 1H), 2.54 - 2.46 (m, 2H), 2.03 (br s, 2H), 1.94 - 1.85 (m, 6H)

[M+H] ⁺ : 522.1

Step 3: Synthesis of compounds WX030A, WX030B.

Compound WX029 (70 mg, 134.12 μmol) was subjected to supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AS-H 250 mm × 30 mm, 5 μm; mobile phase, A: carbon dioxide B: ethanol (0.1% aqueous ammonia); gradient, B%: 30%-30%) to give the chiral isomers WX030A and WX030B with retention times of 3.548 min and 3.847 min, respectively; The ratio is 1:1.

Example 31: WX031

Synthetic route:

Step 1: Synthesis of compound WX031-1.

Compound WX006-4 (50 mg, 201.86 μmol) was dissolved in dichloromethane (5 mL) and treated at 0° C. with triethylamine (51.07 mg, 504.65 μmol) and 4-nitrophenyl chloroformate (48.82 μmol). mg, 242.23 μmol) was added. The reaction was stirred at 25° C. for 2 hours. After completion of the reaction, the reaction solution was directly concentrated to dryness to obtain the crude compound WX031-1, which was directly used in the next reaction.

Step 2: Synthesis of compound WX031.

Compound WX031-1 (80 mg, 193.80 μmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (39.22 mg, 387.60 μmol) and compound BB-19 (43.08 mg, 290.70 μmol). ) was added. The reaction was heated to 60° C. and stirred for 14 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (neutral method) to obtain WX031.

Example 32: WX032

Synthetic route:

Step 1: Synthesis of compound WX032.

Compound WX006-4 (100 mg, 403.72 μmol) was dissolved in dichloromethane (10 mL), triethylamine (122.56 mg, 1.21 mmol) and compound intermediate BB-16 (194.33 mg, 524 .83 μmol) were added respectively and the mixture was stirred at 5-20° C. for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane (40 mL) and washed with water (50 mL). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was separated and purified by thin layer chromatography (eluent: dichloromethane/methanol=20:1) to give compound WX032. This structure also represents their possible isomers.

The examples in Table 7 can be synthesized using BB-15 in step 1 with reference to the synthetic method of step 1 of example 32. The structures in the table also represent their possible isomers.

Each example in Table 8 can be synthesized using WX002-1 in step 1 with reference to the synthesis method of step 1 of example 32. The structures in the table also represent their possible isomers.

Example 36: WX036

Synthetic route:

Step 1: Synthesis of compound WX036-1.

The intermediate compound WX036-1 was obtained with fragment BB-1 by referring to the synthetic method of step 5 of fragment BB-15.

Step 2: Synthesis of compound WX036-2.

Compound BB-27 (130 mg, 240.27 μmol) was dissolved in dichloromethane (10 mL), triethylamine (72.94 mg, 720.81 μmol) and compound intermediate WX036-1 (145.26 mg, 480 μmol). .54 μmol) were added and the mixture was stirred at 20° C. for 15 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane (50 mL) and washed with water (50 mL). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was separated and purified twice by thin layer chromatography (eluent: dichloromethane/methanol=20:1 and petroleum ether/ethyl acetate=2:1) to give compound WX036-2.

Step 2: Synthesis of compound WX036.

Compound WX036-2 (86 mg, 122.12 μmol) was dissolved in dichloromethane (4 mL), diethylamine (446.59 mg, 6.11 mmol) was added, and the reaction was stirred at 20° C. for 12 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane (20 mL) and washed with water (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was separated by high performance liquid chromatography (neutral method) to give WX036, whose structure also represents their possible isomers.

Using fragment BB-16 in step 2, Example 37 of Table 9 can be synthesized by referring to the synthetic method of steps 2-3 of Example 36. The structures in the table also represent their possible isomers.

Example 38: WX038

Synthetic route:

Step 1: Synthesis of compound WX038-1.

BB-24 and BB-2 were used to synthesize the desired compound WX038-1, referring to the step 1 synthesis method for fragment BB-4. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm (br d, J = 8.4 Hz, 1 H), 7.40 (br d, J = 8.4 Hz, 1 H), 4.01 - 3.78 (m, 2H), 3.77 - 3.58 (m, 2H), 3.44 - 3.30 (m, 1H), 3.27 - 3.03 (m, 2H), 3.01 - 2 .87 (m, 1H), 1.61 (br s, 1H), 1.57 - 1.40 (m, 18H), 1.34 (s, 5H), 1.24 (m, 4H)

Step 2: Synthesis of compound WX038-2.

WX038-1 was used to synthesize the targeted compound WX038-2, referring to the synthetic method of step 2 of fragment BB-4. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.82 (m, 1H), 7.53 - 7.44 (m, 1H), 4.18 (m, 1H), 4.07 - 3.88 (m, 2H), 3.82 (m, 2H), 3.61 (m, 1H), 3.40 - 3.22 (m, 1H), 3.20 - 2.98 (m, 1H), 1.61 - 1.60 (m, 1H), 1.53 (s, 9H), 1.50 - 1.33 (m, 18H)

Step 3: Synthesis of compound WX038-3.

Compound WX038-2 (0.85 g, 1.49 mmol) was added to a mixed solvent of dichloromethane (9 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at 25° C. for 1 hour. Reaction completion was detected by liquid chromatography and the reaction was spun dry to give crude product WX038-3 which was used directly in the next reaction.

Step 4: Synthesis of compound WX038-4.

Compound WX038-3 (0.55 g, 1.48 mmol) was dissolved in dichloromethane (20 mL) and saturated aqueous NaHCO ₃ solution was added to adjust pH > 7, followed by 9-fluorenylmethyl chloroformate. Ester (0.77 g, 2.97 mmol) was added and the mixture was stirred at 25° C. for 1 hour. The completion of the reaction was detected by thin layer chromatography and liquid chromatography, the reaction was extracted with dichloromethane (10 mL x 3) at 25°C, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. After that, purification by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) gave compound WX038-4. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89 - 7.66 (m, 5H), 7.60 - 7.44 (m, 4H), 7.44 - 7.34 (m, 5H) , 7.34 - 7.28 (m, 3H), 7.23 (m, 1H), 4.57 - 4.47 (m, 1H), 4.47 - 4.30 (m, 2H), 4 .29 - 4.14 (m, 4H), 4.06 (br s, 2H), 4.01 - 3.91 (m, 1H), 3.89 - 3.68 (m, 1H), 3. 64 - 3.43 (m, 2H), 3.39 - 3.25 (m, 1H), 3.23 - 3.11 (m, 1H), 1.51 (s, 9H)

Step 5: Synthesis of compound WX038-5.

Compound WX038-4 (1.20 g, 1.47 mmol) was dissolved in ethanol (20 mL), concentrated hydrochloric acid (7.35 mL) was added, and then the mixture was stirred at 90° C. for 24 hours. The completion of the reaction was detected by thin layer chromatography and liquid chromatography, and the reaction was concentrated by rotary evaporation, then saturated NaHCO ₃ solution (30 mL) and ethyl acetate (30 mL) were added, and the mixture was diluted with ethyl acetate ( 10 mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give WX038-5. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (m, 4H), 7.59 - 7.46 (m, 4H), 7.41 (m, 4H), 7.34 (m, 5H ), 6.81 (br s, 1H), 4.59 (br s, 2H), 4.46 - 4.16 (m, 5H), 3.94 (m, 3H), 3.75 - 3. 37 (m, 3H), 3.30 - 3.11 (m, 1H), 2.92 (br s, 1H), 2.13 - 2.08 (m, 2H).

Step 6: Synthesis of compound WX038-6.

Using WX036-1 and WX038-5 in Step 1, compound WX038-6 can be synthesized by referring to the synthetic method of Step 1 of Example 29.

Step 7: Synthesis of compound WX038.

Compound WX038 can be synthesized using WX038-6 in Step 1 by referring to the synthetic method of Step 2 of Example 29.

Each example in Table 10 can be synthesized using a different fragment in step 1, referring to the synthetic method of steps 1-2 of example 29. The structures in the table also represent their possible isomers.

Experimental example 1: In vitro activity evaluation

Purpose of the experiment:
_IC50 values were used to assess the ability of test compounds to antagonize CXCR2.

experimental method:
PathHunter® CXCR2 β-arrestin cells (DiscoverX) were grown under standard conditions and seeded at 20 microwells per well in white-walled 384-microwell plates. Cells were incubated at 37° C. for the appropriate time before testing. Test compounds were serially diluted in DMSO with a 3-fold dilution factor to give 8 serially diluted concentrations of test compound. Immediately prior to testing, the serially diluted test compounds described above were further diluted to 5-fold the test concentration in test buffer. Five microliters of further diluted test compound was added to the cells and incubated at 37°C for 30 minutes. Solvent concentration is 1%. Five microliters of 6X EC80 agonist (CXCL8) buffer was added to the cells and incubated at 37°C for 90 minutes. Assay signals were generated by adding 15 μl (50% v/v) of PathHunter detection mixture reagent at once, followed by incubation for 1 hour. Microplates were read by chemiluminescent signal on a PerkinElmer Envision™ instrument. Biological activity of test compounds was analyzed with a CBIS data analysis kit (ChemInnovation, Calif.) and expressed as _IC50 values. Table 12 shows the experimental results.

Conclusion: The compounds of the invention have potent antagonistic activity against CXCR2.

Experimental Example 2: Pharmacokinetic Evaluation of Compounds

Purpose of the experiment:
Pharmacokinetics of Test Compounds in C57BL/6 Mice

Experiment material:
C57BL/6 mice (male, 18-30 g, 7-9 weeks old, Shanghai Lingchang Biotechnology Co., Ltd.)

Experimental operation:
Intravenous administration (1 mpk) is a formulation containing 1% DMSO/10% hydroxypropyl-β-cyclodextrin aqueous solution as vehicle and intragastric administration (5 mpk) is 1% DMSO/1% hydroxypropyl as vehicle. Formulation containing methylcellulose/0.2% Tween 80 in water. Prior to animal experiments, all animals were fasted, fed 4 hours after dosing, and all animals were allowed water ad libitum. Blood sampling, intravenous administration group: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours, intragastric administration group: 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours.

Whole blood samples (0.03 mL) were drawn from the saphenous vein (or other appropriate blood collection site) at designated times and all blood samples were placed in labeled plastic centrifuge tubes containing K2-EDTA anticoagulant. added. After taking blood samples, plasma was separated by centrifugation, immediately placed on dry ice, and samples were stored at low temperatures. Concentrations of all samples are analyzed by LC-MS/MS and the minimum detection limit is 2 nM. A non-compartmental model of the WinNonlin ^™ version 6.3 (Pharsight, Mountain View, Calif.) pharmacokinetic software was used to process mean plasma concentrations and to calculate pharmacokinetic parameters using the linear logarithmic trapezoidal method.

Experimental results are shown in Table 13:

Conclusion: The compounds of the present invention can significantly improve single or partial pharmacokinetic measures in mice.

Experimental Example 3: Evaluation of pharmacokinetic tissue distribution of compounds

Purpose of the experiment:
Pharmacokinetic Tissue Distribution of Test Compounds in Lewis Rats

Experiment material:
Lewis rats (male, 202-239 g, 7-9 weeks old, Beijing VITALRIVER)

Experimental operation:
Intragastric administration (1 mpk) is a formulation containing 1% hydroxypropylmethylcellulose/0.2% Tween 80 in water as vehicle. Prior to animal experiments, all animals were fasted overnight, fed 4 hours after dosing, and all animals were allowed water ad libitum. At the time of blood sampling, Danirixin administration group: 0.25, 1, 8 hours, intragastric administration group: 0.5, 1, 4 hours.

Whole blood samples (0.2 mL) were drawn from the saphenous vein (or other appropriate blood collection site) at designated times and all blood samples were placed in labeled plastic centrifuge tubes containing K2-EDTA anticoagulant. Added to After taking blood samples, plasma was separated by centrifugation, immediately placed on dry ice, and samples were stored at low temperatures. All samples are analyzed by LC-MS/MS with a minimum detection limit of 2 nM. A non-compartmental model of the WinNonlin ^™ version 6.3 (Pharsight, Mountain View, Calif.) pharmacokinetic software was used to process mean plasma concentrations and to calculate pharmacokinetic parameters using the linear logarithmic trapezoidal method.

Experimental results are shown in Table 14:

Conclusion: The compounds of the invention significantly increased the distribution ratio in rat lung tissue.

Experimental Example 4: Therapeutic Effect of Compounds on PPE-Induced COPD Model

Purpose of the experiment:
Therapeutic effect of test compounds on PPE-induced COPD model in C57BL/6 mice.

Experiment material:
Animals: C57BL/6 mice (female, 17.5-18.5 g, 6-8 weeks old)

Drug: Porcine Pancreatic Elastase (PPE) (sigma, 0.068 U/μL); Compound 1 in Figures 1, 2, 3 is Danirixin and Compound 2 is WX006A.

Grouping:
(1) COPD model group (porcine pancreatic elastase model group)
(2) PPE + Danirixin (40mpk)
(3) PPE + Danirixin (120mpk)
(4) PPE+ WX006A (4mpk)
(5) PPE+ WX006A (12mpk)

Experimental operation:
1. Modeling method: PPE drip after tongue.
2. Administration method: 1% DMSO/1% hydroxypropyl methylcellulose/0.2% Tween 80 aqueous solution was used as a solvent, and the dose was 200 μL/animal, intragastric administration. Dosing daily for a total of 4 weeks.
3. Experimental endpoint: On day 29, mice were sacrificed, samples were collected and flow cytometry was performed.

flow cytometry

After 4 weeks of administration, mouse blood, bronchoalveolar lavage fluid, and lung tissue were collected, and the ratio of inflammatory cells was measured.

1) Alveolar lavage cells: Mice were sacrificed, the neck dissected, and the trachea exposed for tracheal intubation. Wash with 1 mL 4° C. cold sulfate buffer, wash 3 times, and mix the washes. After centrifugation at 1200 rpm/min for 5 minutes, the supernatant was discarded to collect the cell suspension.
2) Collect mouse blood and lung tissue, lyse red blood cells from the blood, wash, prepare cell suspension, mince lung tissue, and digest with type I collagenase at 37°C for 1.5 hours. A cell suspension was prepared after filtration, red blood cell lysis, and washing.
3) Counted and divided the cell suspension into flow tubes.
4) CD45, Ly6c, Ly6g, and CD11b flow-type fluorescent antibodies were marked after splitting.
5) After washing the cells, flow cytometry was used to detect the percentage of neutrophils and monocytes within the CD45 + cells.

Results of the experimental data are shown in FIGS. It is concluded that in the PPE-induced mouse COPD model, the compounds of the invention significantly inhibit the proportion of neutrophils in lung tissue and are superior to the positive control Danirixin. The compounds of the present invention and Danirixin high dose (120 mpk) have a significant reducing effect on the ratio of neutrophils to monocytes in bronchoalveolar lavage fluid and show good inhibitory effects on inflammation. At the same time, the compounds of the invention are able to achieve significant anti-inflammatory effects at low doses (4 mpk).

Claims (16)

A compound of formula (II), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

(here,
T ₁ is selected from C(R ₂ R ₃ ) and N(R ₄ );
ring A is selected from 5- to 6-membered heteroaryl and phenyl, said 5- to 6-membered heteroaryl and phenyl optionally substituted by 1, 2 or 3 R _a ;
R ₁ is C _1-6 alkyl, NH ₂ —(C═O)—C _1-3 alkyl-, 5-10 membered heteroaryl-C _1-3 alkyl-, C _3-7 cycloalkyl, 5-9 selected from membered heterocycloalkyl, 5- to 10-membered heteroaryl, phenyl, —C _1-6 alkyl-phenyl, said C _1-6 alkyl, NH ₂ —(C═O)—C _1-3 alkyl-, 5 ~10 membered heteroaryl-C _1-3 alkyl-, C _3-7 cycloalkyl, 5-9 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, -C _1-6 alkyl-phenyl is optionally substituted by 1, 2 or 3 R,
R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl optionally substituted by 1, 2 or 3 R _b is,
R ₄ is selected from H and C _1-3 alkyl optionally substituted by 1, 2 or 3 R _c ;
each R _a is independently selected from H, F, Cl, Br, I, OH, _NH2 and C _1-3 alkyl optionally substituted by 1, 2 or 3 R′;
_Rb and _Rc are each independently selected from H, F, Cl, Br, I, OH and _NH2 ;
Each R is independently H, F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkyl-(C=O)-NH-, C _1-3 alkyl- selected from O-(C=O)-NH-, C _3-6 cycloalkyl-(C=O)-NH- and C _1-6 alkyl-O-(C=O)-, said C _1-3 Alkyl, C _1-3 alkyl-(C=O)-NH-, C _3-6 cycloalkyl-(C=O)-NH- or C _1-6 alkyl-O-(C=O)- is selected optionally substituted by 1, 2 or 3 R',
each R' is independently selected from F, Cl, Br, I, OH and _NH2 ;
Said 5- to 6-membered heteroaryl, 5- to 10-membered heteroaryl and 5- to 9-membered heterocycloalkyl are each independently represented by 1, 2, 3 or 4 groups of -NH-, -C(=O)-, - It includes a heteroatom or heteroatom group selected from O—, —S— and N. ) R is F, Cl, Br, I, OH, _NH2 , Me, Et,

is selected from said Me, Et,

is optionally substituted by 1, 2 or 3 R' and/or
each R _a is independently selected from H, F, Cl, Br, I, OH, NH2 and Me; and/ _or
R2 and R3 _are each independently selected from H, F, Cl, Br, I, OH, NH2 and Me, and _{/ or}
2. The compound of Claim 1, a tautomer or stereoisomer thereof, _or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H and Me . R is F, Cl, Br, I, OH, _NH2 , Me,

3. The compound of claim 2, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from: R ₁ is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, NH ₂ —(C═O)—CH ₂ —, isoindoline-1,3-dione-(CH ₂ ) ₂ —, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-diazacycloheptyl, —C _1-4 alkyl-phenyl, 2-azaspiro[3.3]heptyl and 7-azaspiro[3.5 ] nonyl, said methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, NH ₂ —(C═O)—CH ₂ —, isoindoline-1,3-dione-(CH ₂ ) ₂ —, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-diazacycloheptyl, —C _1-4 alkyl-phenyl, 2-azaspiro[3.3]heptyl and 7-azaspiro[ 3.5]nonyl is optionally substituted by 1, 2 or 3 R ; and/or
Said ring A is selected from furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl and phenyl; said furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl and phenyl are optionally A compound according to any one of claims 1 to 3, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is substituted by R _a . R ₁ is Me, Et,

is selected from said Me, Et,

is optionally substituted by 1, 2 or 3 R ; and/or
Ring A is

is selected from the aforesaid

is optionally substituted by 1, 2 or 3 R _a , a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt. R ₁ is Me;

and/or
Ring A is

6. The compound of claim 5 , a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from : structural unit

A compound according to any one of claims 1 to 3, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from: The compound is

is selected from
here,
R ₁ is as defined in claims 1 or 4-6 ,
R ₂ and R ₃ are as defined in claim 1 or 2 ,
_R4 is as defined in claim 1 or 2 ,
Ring A is as defined in claims 1 or 4-6 ,
7. Any of claims 1 to 6 , characterized in that the carbon atoms marked with "*" are chiral carbon atoms and are present in (R) or (S) single or enantiomerically enriched forms. A compound according to claim 1, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound is

is selected from
wherein R ₁ is as defined in claims 1 or 4-6 ;
R ₂ and R ₃ are as defined in claim 1 or 2 ,
_R4 is as defined in claim 1 or 2 ,
9. Compounds according to claim 8 , characterized in that the carbon atoms marked with "*" are chiral carbon atoms and exist in (R) or (S) single or enantiomerically enriched forms. , a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound is

is selected from
here,
m is 0, 1 or 2;
n is 1 or 2,
R is as defined in any one of claims 1-3;
R ₂ and R ₃ are as defined in claim 1 or 2 ,
_R4 is as defined in claim 1 or 2 ,
R _a is as defined in claim 1 or 2 ;
10. Compounds according to claim 9 , characterized in that the carbon atoms marked with "*" are chiral carbon atoms and exist in (R) or (S) single or enantiomerically enriched forms. , a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof. A compound, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof , characterized in that it is selected from the following :

The compound is

12. The compound of claim 11 , a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from: The compound is

12. The compound of claim 11 , a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from: A therapeutically effective amount of the compound according to any one of claims 1 to 13 , a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier as an active ingredient A pharmaceutical composition comprising: A compound according to any one of claims 1 to 13 , a tautomer or stereoisomer thereof or a pharmaceutically acceptable salt thereof or a compound according to claim 14 for use in treating a CXCR2- related disease. pharmaceutical composition of The medicament is a compound according to any one of claims 1 to 13, a tautomer or stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof according to claim 14 for use in the treatment of COPD . pharmaceutical composition of

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